The series begins with Philip J. Fry, a New York City slacker and pizza delivery man, who is cryogenically frozen by accident on New Year's Eve, 1999. He is defrosted one thousand years later on December 31, 2999 and finds himself in New New York City. Fry's attempt to escape from his now-mandatory job assignment as a delivery boy ends when he is hired on at Planet Express, a small intergalactic package delivery company run by his distantly descended nephew, as a delivery boy. The series covers the adventures of Fry and his colleagues as they travel around the universe making deliveries on behalf of Planet Express.

The futuristic time frame allowed the show's writers to be creative with their humor by introducing ideas and events from pulp science fiction of the mid 20th century into the series.

The Professor often makes passing references to the brutal deaths of previous employees; the crew prior to Fry's arrival was said to have been devoured by a space wasp, while another was stung to death by a swarm of gigantic bees.

The Planet Express ship is helmed by Leela, with Bender serving as cook and Fry as delivery boy. Amy and Dr. Zoidberg accompany the crew as needed. The ship is equipped with autopilot and a shipboard artificial intelligence. Nearly every mission that the Professor assigns his crew is unusually dangerous.

The setting is first and foremost a backdrop for humor, and the show is not above committing continuity errors if they serve to further the gags. The capabilities of many things vary according to what is most appropriate for the situation at hand.

The visually retro-futuristic world of Futurama is not a utopia but neither is it a dystopia. Unlike past cartoons like The Jetsons, which showed an efficient, clean, happy future, Futurama portrays a less idealistic view, with humans still dealing with many of the same basic problems of the 20th century. The show's vision of the future is very similar to the present in many ways: the same political figures and celebrities that we know today survive as heads in jars, a method invented by Ron Popeil; television remains the primary means of entertainment; the Internet is still slow and filled with pornography, and problems such as global warming, inflexible bureaucracy, and substance abuse are still pressing issues.

Race issues in 3000 are now centered around relations among humans, aliens, and robots. A common clash between the former two is alien immigration plaguing Earth. A specific issue on Earth is the large population of super-intelligent/super-incompetent robots (such as homeless robots and orphan children robots, like Tinny Tim); they are generally lazy and surly, and often unwilling to assist their human creators.

Despite this, Futurama's world also showcases numerous technological advantages that have been developed by the year 3000. Wheels used in transportation have been made obsolete by hover technology, to the point that 31st century characters do not know what a wheel is. Among the robots, spaceships, and floating buildings, Professor Farnsworth introduced many memorable new inventions such as the Smell-o-scope, the What-if Machine, and the Parabox. Less inspiring 31st century innovations include coin-operated Suicide Booths (said in the show to have been in business since 2008) and Soylent Cola (the taste "varies from person to person").

Some of the show's humor comes from passing references to historical events of the past thousand years. For example, in the time that has passed formerly-endangered owls and marmosets have emerged as the primary urban pests, at the expense of rats and pigeons. Los Angeles has become a wasteland, Fry mistaking it for New New York in the year 4000 after believing he had been cryogenically frozen for a further 1000 years. In another episode, Pamela Anderson mentions that she won an Academy Award for Baywatch: The Movie, the first ever to be filmed entirely in slow-motion.

The suicide booths are not the only sign of a devaluing of human life, despite their popularity. Murder is discussed casually, as if there were little or no penalty for it. ("Could you pick me up a license to kill?" "Sure. Bare hands or weapons?" "Hm. What does piano wire count as?") Grievous bodily injuries are shrugged off or treated with a sort of mild uncaring, perhaps in reference to the highly advanced medical technology as well as the general disregard for the lives of others or oneself. This sort of indifference to death and pain may be partly a mockery of the reactionary trend of citing rising crime statistics as a symptom of human life losing its value, partly on account of the failure to take proper precautions or care of themselves because of the availability of medicines and operations, and partly callousness (such as Fry's happy declaration that his organ transplant came from a guy who liked to ride motorcycles).

Futurama's universe also makes several bold predictions about the future of linguistics. In "A Clone of My Own" (and "Space Pilot 3000"), it is implied that French is now a dead language, and that the official language spoken by the French will then be English (in the French version of Futurama, German is substituted for French as the dead language).

English itself has also evolved from today, but still remains comprehensible. These changes include the disuse of the word Christmas in favor of Xmas (with the X pronounced, as in "ex-mas") and the pronunciation of ask metathesizing as "aks". Ironically, "aks" represents an earlier pronunciation of the word, with the modern "ask" an innovation, so the 31st century sees the word coming full circle.

The show also often makes use of a pair of alien alphabets in background signage. The first is a simple one-to-one substitution cipher from the Latin alphabet, while the second uses a more complex modular addition code (officially an ancient alien language predating the universe). They often provide additional jokes for fans dedicated enough to decode the messages.

Numerous other galaxies have been colonized or have made contact by the year 3000. Much of the Milky Way galaxy now operates under the Earth government's sphere of influence, similar to America's influence on world politics today. Apparently, Earth is in the process of embarking on a long-term campaign to conquer and/or eliminate all other worlds/races not allied with it. This campaign is spearheaded by 25-star General Major Weeblo Zapp Brannigan, a conceited, self-absorbed, trouserless individual who makes regular appearances throughout the series.

Earth has a unified government called the United States of Earth headed by a single President of Earth. It seems that various sub-states may have prime ministers and similar leaders, much like the current American system of governors. This world government seems to be quite US-centric as Earth's capital is Washington, D.C. and the flag of Earth looks like the Flag of the United States, but with an image of the Earth (with the U.S. visible) where the stars are today. Citizens of Earth are called Earthicans.

The organization of political parties in Futurama is similar to the American two-party system with a number of third parties. The two main parties are the Tastycrats and the Fingerlicans, whose names sound similar to the current American parties, the Democrats and Republicans.

Despite having been elected President of the United States twice, the head of Richard Nixon is elected President of Earth by exploiting the fact that his old body is not being elected, and Earthican law only stipulates that no body can be elected more than twice. Nixon buys Bender's robotic body from a pawn shop to serve as his new body. After the Planet Express crew manages to retrieve it, Nixon's head is mounted on a gargantuan, weaponized cyborg body, helping to sway the robot vote. At times, Nixon's head is carried by the Secretary of Transportation or the headless body of Spiro Agnew. At the end of Futurama's last episode, however, the Robot Devil drags Nixon's head back to Hell, so the status of his presidency is now in question.

Earth's national holiday appears to be "Freedom Day", which is traditionally celebrated by doing whatever one wants without regard to the consequences, as well as nude hot tubbing parties, and by dancing and chanting, "Freedom, freedom, freedom, oy!"

Mars has been terraformed to a great degree (it is now the home of many wealthy socialites), and is home to Mars University. The Western Hemisphere of the planet is currently owned by the Wongs, parents of Planet Express intern Amy Wong.

Earth's moon is still mostly unsettled with the exception of some farms, but houses an amusement park (heavily parodying Disney theme parks even to the motto: "The Happiest Place Orbiting Earth"), and is the sole tourist attraction. Citizens of the 31st century have lost all knowledge of the lunar landing, mistaking Ralph Kramden of The Honeymooners for a typical 20th century astronaut due to his common phrase, "One of these days, Alice. Bang! Zoom! Straight to the moon!".

The Democratic Order of Planets (DOOP) was founded in 2945 after the Second Galactic War (a parallel to the United Nations' founding in 1945 after World War II). This organization, described by Prof. Farnsworth as being "similar to the United Nations... or like the 'Federation' from your Star Trek program", includes Earth and many other worlds. Earth sometimes acts unilaterally without the aid of other DOOP members. The inhabitants of Omicron Persei 8 are frequently engaged in conflicts with DOOP. The DOOP symbol has rotational symmetry.

Despite the existence of DOOP, interplanetary relations are poor, with constant wars and invasions, often poorly planned and fought for foolish and unnecessary reasons.

The series featured a bitter conflict between Earth and Spheron 1, a planet inhabited by giant, bouncing balls. A victorious war with the Arachnid homeworld of Tarantulon VI resulted in a silk surplus, which in turn led to a $300 tax refund from the head of Richard Nixon, the ruling President of Earth.

There is also at least one rogue colony of robots that kills humans on sight (this being Chapek 9, a reference to Karel Čapek who coined the term robot). A planet named Arrakis exists, a tip-of-the-hat to Frank Herbert's Dune novels. The universe ends after Dog Doo 7. At the edge of the universe, one can witness the alternate cowboy universe. It is unknown if it's possible to travel between these universes freely.

Since a matter of years after the Big Bang, an eternal war has been waged across space between the Nibblonians (Nibbler's race) and the Brainspawn (evil floating giant brains with telekinetic and telepathic powers). The war recently made its final end when the Nibblonians used Fry to sneak a bomb into the Brainspawn's main base that would seal them into a pocket dimension prison.

Religion has changed quite a bit since the year 2000. Christianity, Judaism, Islam, Hinduism, and Buddhism have all merged into one Amalgamated Church. There is some form of Space Catholicism, led by the reptilian Space Pope (Crocodylus pontifex) and based upon a platform of discouraging love between robots and humans (one episode, I Dated a Robot, dealt with this by allowing people to download celebrity personalities into robot copies. However, the episode did not feature the Space Pope, being little more than a pro-RIAA/anti-MP3 message). Oprahism and Voodoo are now mainstream religions. (Waltermercadismo is also mentioned in the Latin American version.)

Some of today's holidays still exist, but with slightly different mascots. Christmas, now Xmas, is celebrated with the fear of a giant robotic Santa Claus, who is located on Neptune. He was originally created and programmed by Mom's Friendly Robot Co. to judge people, whether naughty or nice, and distribute presents accordingly, but his standards were set so high that he invariably deems everybody naughty (except for Dr. Zoidberg), and attempts to punish them on Christmas Eve if they are caught outdoors after sun-down. Hanukkah is now represented by the Hanukkah Zombie and Kwanzaa by Kwanzaabot.

Robot religions exist as well, with the most popular being the quasi-Christian religion of Robotology, which has its Hell located in an abandoned New Jersey amusement park, presided over by the crafty Robot Devil. Robot Jews exist as well, although all we know about them is that they hold functions to celebrate a robot becoming a "Bot Mitzvah". They believe that Robot Jesus was a very well built robot, but he was not their messiah, and they do not permit decapodians to attend their functions (presumably because shellfish aren't kosher, although ironic since the Decapodians are a parody of Jewish stereotypes).

Over the years, as life began to imitate Star Trek more and more, the sci-fi series evolved into an enormous mainstream religious cult that swept the world. This caused the "Star Trek Wars" (not to be confused with the "Star Wars Trek", the mass migration of Star Wars fans). The destruction because of the "Wars" ultimately led to its banning by the Earth government and the execution of its followers "in the manner most befitting virgins", i.e., by being thrown into a volcano to the phrase "He's dead, Jim." By the year 3000, even discussing the show is a serious legal offense. (It is mentioned with no penalties, however, once by Hermes Conrad while describing the Democratic Order Of Planets, and again in the episode where the Planet Express crew uses the Internet, and once more in the first episode when Fry says the doors are just like the ones from Star Trek.) There is little mention of what happened to The Next Generation and the other spinoffs, but the head of Jonathan Frakes lives on in a glass jar (normally on a shelf directly behind the jar housing the head of Leonard Nimoy). Star Trek: The Pepsi Generation does, however, get an Oscar nomination for best soft-drink product placement.