He is known for his roles as Quinn Mallory in the television series Sliders, Andrew Clements in My Secret Identity, Vern Tessio in the film Stand by Me (1986), Joe in Joe's Apartment (1996), Frank Cushman in Jerry Maguire (1996), Derek in Scream 2 (1997), Michael in Tomcats (2001), Charlie Carbone in Kangaroo Jack (2003), and Detective Woody Hoyt on the NBC drama Crossing Jordan.

Currently, he voices Commander Jack Ransom on the animated series Star Trek: Lower Decks, is co-host of The Talk, and hosts a version of Pictionary syndicated on Fox stations.

[citation needed] Shortly after turning eleven, he landed his first feature film role as the character Vern Tessio in Rob Reiner's Stand by Me.

During a summer break from NYU, Jerry starred in the feature film Calendar Girl alongside Jason Priestley and Gabriel Olds.

O'Connell has since gone on to star in such films as Jerry Maguire, Body Shots, Mission to Mars, Tomcats, Scream 2, and Kangaroo Jack.

O'Connell served as executive producer and received a "story by" credit on the film, which starred Katie Holmes and Michael Keaton.

O'Connell starred as Detective Woody Hoyt on the NBC crime drama Crossing Jordan (2001) until its cancelation in May 2007, and was engaged to actress Rebecca Romijn.

The play, directed by Sam Gold, opened on November 20, 2011, starring Alan Rickman, Lily Rabe, Hamish Linklater and Hettienne Park.

In April 2015, O'Connell returned to Broadway in the comedy Living on Love, with Renee Fleming, Anna Chlumsky and Douglas Sills.

[25] He also starred in a Canadian police comedy-drama series called Carter, which was North Bay, Ontario and aired for two seasons.

[26] In January 2020, O'Connell appeared in the Roundabout's American Airlines Theatre's Broadway revival of A Soldier's Play as Captain Taylor in an ensemble cast headed by David Alan Grier and Blair Underwood.

[28] That same month, he hosted a test-run of a new syndicated version of Pictionary on Fox stations, which was successful enough to launch with a full season in fall 2022.

[1] O'Connell is a regular and commonly recurring guest on the Barstool Sports podcast Pardon My Take, where he discusses his passion for fantasy football and his fandom for the show.

As of January 2025, O'Connell's role as general manager of PMT's fantasy team is in jeopardy due to results of the 2024 season.