In 2001, Stump co-founded Fall Out Boywith guitarist Joe Trohmanand bassist Pete Wentz Stump first joined Fall Out Boyas a drummer, but his singing talent was soon discovered even though he had no prior experience as a vocalist. Originally, Stump was only the band's vocalist, but after the departure of two members following the release of Fall Out Boys Evening Out with Your Girlfriend, he also began playing guitar for the band. At this point, present day drummer Andy Hurleywas also brought into the band.

The band's first full-length album Fall Out Boys Evening Out with Your Girlfriend was released in 2003 on Uprising Records, although they shortly left the label to sign to Fueled By Ramen. They released Take This To Your Grave in May, 2003, their second full-length album which helped them earn a fan base and some minor success. In 2003, Stump and his band mates signed with Island Records and released the acoustic-based EP My HeartWill Always Be the B-Side to My Tongue CD and DVD in 2004. This was followed with their second studio album, From Under The Cork Tree.

In Fall Out Boy Stump writes the majority of the music for the band, while bassist Pete Wentzwrites the majority of the lyrics.

As a producer, Stump has worked with The Hush Sound on Like Vines and Gym Class Heroes on As Cruel As School Children. He has also produced Cobra Starship's record ¡Viva La Cobra!. He's also produced a track titled "Little Weapon" on Lupe Fiasco's record The Cool, and is said to be currently working in production with The Cab, Tyga, and Gym Class Heroes. In addition to producing albums, Stump has also remixed various tracks for soundtracks or special releases. These include a "Queen Of Apology" remix for The Sounds on the Snakes on a Plane soundtrack, "Sugar We're Goin Down" remix on the From Under the Cork Tree special edition release for Fall Out Boy and "Pace Yourself" for The Higher on their album On Fire.

Guest vocal appearances include Gym Class Heroes' "Clothes Off!", and "Cupid's Chokehold", October Fall's "Second Chances," Knockout's "Breakaway," Motion City Soundtrack's "Everything Is Alright," The Hush Sound's "Don't Wake Me Up," and Misery Signals' "One Day I'll Stay Home". Stump and Wentz have both added guest vocals to Damnation A.D.'s song "If You Could Remember" and Timbaland's "One & Only".