He first gained widespread attention during his tenure as a cast member on the NBC sketch comedy series Saturday Night Live from 1986 to 1995, where he anchored the show's news parody segment Weekend Update.

[5] He graduated from St. Joseph High School in Trumbull, Connecticut, in 1971 and earned a bachelor's degree in marketing from Sacred Heart University.

[8][6] He had been doing stand-up for six years when he made his network television debut on The Tonight Show Starring Johnny Carson in 1984.

By the time he departed in 1995, he had held the record for longest-tenured cast member at nine seasons, which has since been surpassed by Tim Meadows, Darrell Hammond, and Kenan Thompson.

[6][13] Other films in which he has since appeared include Happy Gilmore,[14][15] The Wedding Singer,[14] Anger Management, Little Nicky, Just Go with It,[16] Daddy Day Care, Good Boy!, and Aliens in the Attic (2009).

The most popular episode was titled "The New Writer" when he starts hanging around the office so much that Hank (played by actor Jeffrey Tambor) is worried Nealon is trying to steal his job.

[24] Nealon had a recurring television role on the 2002–06 CBS comedy Still Standing playing Ted Halverson, the Millers' competitive and religious neighbor.

[36] Nealon produces and edits the entire show by himself, recording simply using a selfie stick and a camera drone.

[39] During this time, Nealon, who has been a vegetarian since 1989,[40] became active in the animal rights movement; he has supported PETA,[41] the Amanda Foundation, Farm Sanctuary,[8][42] the Washington Wildlife Alliance, The Ark Trust's Genesis Awards, and also Meat Out.

[47] On February 22, 2006, Nealon contributed an opinion article to The New York Times about having his phone tapped and his police records searched by Hollywood private investigator Anthony Pellicano,[48] who was later convicted of crimes including racketeering and illegal wiretapping.

[49] Nealon is a fixture on the European melodic rock scene both as a fan, and as a benefactor; in 2019 he used his fame to organize a benefit for close friend and ailing rocker Tony Mills.

[50] On May 15, 2022, Nealon was awarded a Doctorate of Humane Letters, Honoris Causa, by his alma mater, Sacred Heart University.