[2] As a voice actor he is known for portraying the Yellow M&M in commercials since 1996, Cave Johnson in the video game Portal 2 (2011), White Knight in Generator Rex (2010–2013), Tenzin in The Legend of Korra (2012–2014), Stanford "Ford" Pines in Gravity Falls (2015–2016), Kai in Kung Fu Panda 3 (2016), Mayor Leodore Lionheart in Zootopia (2016), Martin Smarty in Kim Possible (2002–2007), Nolan Grayson / Omni-Man in Invincible (2021–present) and Mortal Kombat 1 (2023), and General Ketheric Thorm in the video game Baldur's Gate 3 (2023).

[9] He also played the role of Jigger in a revival of Carousel with the Houston Grand Opera and starred in the 1987 Off-Broadway musical Birds of Paradise.

Among his more notable roles are Dr. Emil Skoda, a police psychiatrist whom Simmons played on three of the four incarnations of Law & Order and New York Undercover, and sadistic neo-Nazi inmate Vernon Schillinger on the prison drama Oz.

Simmons starred in several films produced or directed by his friend Jason Reitman, including Thank You for Smoking, Juno, Up in the Air, and Jennifer's Body.

[20] From 2015 to 2016, he voiced the scientist Stanford Pines on the Disney XD animated series Gravity Falls for the second season.

[21] In the 2014 drama film Whiplash, Simmons played Terence Fletcher, an intensely demanding and abusive bandleader at the fictional Shaffer Conservatory of Music, who bullies and cajoles his student, Andrew Neiman (Miles Teller).

"[23] Entertainment Weekly summed up the reaction by saying Simmons's performance "has been universally praised" and that he was "a leading contender for Best Supporting Actor.

Several of these have arisen from his J. Jonah Jameson character in Raimi's Spider-Man films, including voices of two newspaper editors in episodes of the eighteenth season of The Simpsons.

[29] Likewise, Simmons voiced an editor-in-chief of a newspaper (with Jameson's appearance and mannerisms) for a 2013 episode of The Hub's Pound Puppies.

In 2017, Simmons portrayed Commissioner James Gordon in Joss Whedon's film Justice League, part of the DC Extended Universe.

[37] In the field of television commercials, Simmons is widely known for being the voice of the yellow M&M, a role he has played since 1996, replacing John Goodman.

[39] In 2017, Simmons had a small cameo for a role in SpongeBob SquarePants of Conductor Maestro Mackerel for the episode "Snooze You Lose" in season 10.

[40] In 2019, Simmons reprised his role of J. Jonah Jameson in the Marvel Cinematic Universe (MCU) film Spider-Man: Far From Home, as a cameo in the mid-credits scene.

[45] He also narrated the Netflix limited series documentary Coronavirus, Explained[46] and co-starred in the critically acclaimed sci-fi/comedy Palm Springs, which premiered at the Sundance Film Festival in January and on Hulu in July.

[19] In 2021, Simmons provided the voice for Omni-Man in the animated show Invincible, played the role of George Zax, CEO of a family-owned and operated pharmaceutical company on the fourth season of Goliath, and also appeared in the military science-fiction film The Tomorrow War.

In 2021, Simmons portrayed William Frawley in the Amazon movie Being the Ricardos, for which he received his second Academy Award nomination.

In 2005, Simmons also reprised his role of J. Jonah Jameson, as a voice actor, for the PSP version of Spider-Man 2: The Video Game.

[19] Simmons appears as the anti-communist U.S. President Howard T. Ackerman in the video game Command & Conquer: Red Alert 3 and for a series of promotional advertisements parodying the 2008 presidential elections.

[19] In April 2011, he appeared in Portal 2 as the voice of Aperture Science founder Cave Johnson,[52] a performance that was lauded as the "surprise star turn" of the game.

[53][failed verification] He reprised his role as Cave Johnson in the 2015 video game Lego Dimensions, the 2022 video game Aperture Desk Job,[54] and was introduced to be a part of the Dota 2 2022 Battle Pass: Part II in an Announcer and Mega Kills Packs.

[65] He is a member of Phi Mu Alpha Sinfonia, the men's music fraternity, and was initiated in 1975 at the University of Montana.