From 2000 until his departure from the show in 2004, Fallon co-anchored Saturday Night Live's "Weekend Update" segment with Tina Fey. He was also an impressionist, portraying Pat O'Brien, Osama bin Laden, Jeff Zucker, Dennis Miller, Robin Williams, Carson Daly, Chris Rock, Ryan Seacrest, Richard Simmons, Jerry Seinfeld, Adam Sandler, Howard Stern, Mick Jagger, Hilary Swank, and French Stewart.

Fallon had a famous tendency to forget lines or break character by laughing in the middle of sketches, especially around fellow cast members and friends Horatio Sanz and Will Ferrell.

In 2002, Fallon released the comedy album The Bathroom Wall which was nominated for a Grammy in 2003 for Best Spoken Comedy Album.

He wrote a book in 1998 called I Hate this Place: The Pessimist's Guide to Life with sister Gloria about his brief time in Los Angeles. In 2005 he released a children's book called Snowball Fight! based on a song from his album.

Fallon was chosen for People Magazine's "50 Most Eligible Bachelors" as well as People Magazine's "50 Most Beautiful People in the World" in 2002.

Following the Boston Red Sox's World Series clinching game over the St. Louis Cardinals in 2004, Fallon ran onto the field at Busch Stadium with Drew Barrymore to film a scene for their movie Fever Pitch. The move angered numerous Red Sox fans, who felt their 86-year moment-in-waiting had been cheapened by Fallon.

In 2006, Fallon starred in a Pepsi television commercial with actress Parker Posey. In the ad, the two can be seen dancing and jumping around to the song Streamline by Newton.