John Belushi was born in Chicago, Illinois, the son of Agnes Belushi (née Samaras), a first generation Albanian-American, and Adam Belushi (b. 1918), an Albanian immigrant and restaurant operator who left his native village, Qytezë, in 1934 at the age of sixteen. The family's name at the time of immigration was Bellios, or Belliors. Belushi was raised in the Albanian Orthodox church and grew up outside Chicago in Wheaton with a brother Jim, five-and-a-half years his junior. He attended Wheaton Central High School, where he met his future wife, Judy Jacklin.

Belushi's first big break as a comedian occurred in 1971, when he joined The Second City comedy troupe in Chicago. He was cast in National Lampoon's Lemmings, a parody of Woodstock, which played Off-Broadway in 1972 and also showcased future Saturday Night Live (SNL) performers Chevy Chase and Christopher Guest.

From 1973 to 1975, National Lampoon Inc. aired The National Lampoon Radio Hour, a half-hour comedy program syndicated across the country on approximately 600 stations. Other players on the show included future SNL regulars Gilda Radner, Bill Murray, Brian Doyle-Murray and Chevy Chase. Belushi married Judy Jacklin (Judy Pisano), an associate producer of The Radio Hour. A number of comic segments first performed on The Radio Hour would be translated into SNL sketches in the show's early seasons.

Belushi achieved national fame for his work on Saturday Night Live, which he joined as an original cast member in 1975. Between seasons of the show, he made one of his best-known movies, Animal House. As several Belushi biographies have noted[specify], on John's 30th birthday (in 1979), he had the number one film in the U.S. (Animal House), the number one album in the U.S. (The Blues Brothers: Briefcase Full of Blues) and Saturday Night Live was the highest-rated late night television program.

When interviewed for retrospectives on John Belushi, Dan Aykroyd told stories of John often finishing SNL rehearsals, shows or film shoots and, exhausted, simply walking unannounced into nearby homes of friends or strangers, scrounging around for food and often falling asleep, unable to be located for the following day's work.[citation needed] This was the impetus for the SNL horror-spoof sketch "The Thing That Wouldn't Leave", in which Belushi torments a couple (played by Jane Curtin and Bill Murray) in their home looking for snacks, newspapers and magazines to read, and taking control of their television. In an unfortunate foreshadowing, during the opening an episode of SNL that aired on December 17, 1977, Belushi, while in character as himself, quipped, "I plan to be dead by the time I'm 30." SNL also featured a short film by writer Tom Schiller called "Don't Look Back In Anger", where Belushi, playing himself as an old man and the last-surviving SNL cast member, visits the graves of his now-former cast members. Ironically, Belushi was the first SNL cast member to die.

Belushi left Saturday Night Live in 1979 to pursue a film career. Belushi would make four more movies; three of them, 1941, Neighbors, and most notably The Blues Brothers were made with fellow SNL alumnus Dan Aykroyd.

Dan Aykroyd wrote the roles of Dr. Peter Venkman in Ghostbusters and Emmett Fitz-Hume in Spies Like Us with Belushi in mind, and the roles were actually played by Belushi's former SNL castmates Bill Murray and Chevy Chase, respectively.

Released in September 1981, the romantic comedy Continental Divide starred Belushi as Chicago home town hero writer Ernie Souchack who gets put on assignment researching a scientist studying birds of prey in the remote rocky mountains.

At the time of his death, Belushi was pursuing several movie projects, including Noble Rot, an adaptation of a script by former The Mary Tyler Moore Show writer/producer Jay Sandrich entitled Sweet Deception; noble rot is a benevolent fungus that can infect wine grapes on the vine, helping to produce high quality sweet wines.

The "College" sweatshirt Belushi wore in National Lampoon's Animal House was purchased in Carbondale, Illinois, when his brother, Jim, was a student at Southern Illinois University Carbondale.