Krumholtz is best known for portraying Bernard in The Santa Clause franchise (1994–present), Michael Eckman in 10 Things I Hate About You (1999), Goldstein in the Harold & Kumar film trilogy (2004–2011), Charlie Eppes in the CBS drama series Numb3rs (2005–2010), and Isidor Isaac Rabi in Oppenheimer (2023).

Krumholtz has also had other supporting roles in notable films such as Addams Family Values (1993), The Ice Storm (1997), Slums of Beverly Hills (1998), Ray (2004), Serenity (2005), Superbad (2007), Hail, Caesar!

Along the way, he had the opportunity to work with Jason Bateman (Chicago Sons, 1997), Tom Selleck (The Closer, 1998), Jon Cryer (The Trouble with Normal, 2000), and Rob Lowe (The Lyon's Den, 2003).

He broke out of the children's movie genre with The Ice Storm (1997), directed by Ang Lee, and Slums of Beverly Hills (1998), starring Alan Arkin and Natasha Lyonne.

In 1999, Krumholtz starred as Michael Eckman in the popular teen movie 10 Things I Hate About You with Larisa Oleynik, Joseph Gordon-Levitt, Julia Stiles, and Heath Ledger.

It was the role of Yussel that brought Krumholtz to the attention of actor and filmmaker Edward Burns, who cast him in the independent film Sidewalks of New York (2001).

Krumholtz carried his first leading role in a released American film when he starred in Big Shot: Confessions of a Campus Bookie (2002), which premiered on FX Networks.

Krumholtz played Benny Silman, a college student and campus bookmaker, who was jailed for his part in shaving points off key Arizona State basketball games.

Most recently, in early 2006, Krumholtz's 2003 film Kill the Poor screened in New York City at IFC Center and across the country on Comcast's On Demand cable service.

[12] Krumholtz portrayed Charlie Eppes, a genius who used mathematics to help his FBI agent brother Don (Rob Morrow) solve crimes.

The cast of Numbers also included Judd Hirsch and Peter MacNicol, who appeared with Krumholtz in Addams Family Values as a camp counselor.

[15] In 2015, he played the title role wearing heavy prosthetics as an elderly Jewish woman in the IFC comedy series Gigi Does It which he wrote and co-created with Ricky Mabe and Zach Golden.

In fall 2022, Krumholtz returned to the stage to play the role of Hermann Merz in the original Broadway cast of Tom Stoppard’s Leopoldstadt at The Longacre Theater in New York City.