David Krumholtz was born in Queens, New York, the son of Judy, a dental assistant, and Michael Krumholtz, a postal worker. He grew up in a "very working-class, almost poor" Jewish family. Krumholtz began his acting career at the age of thirteen when he followed his friends to an open audition for the Broadway play Conversations with My Father (1992). Though he did not expect to get the part, and did not even care, he won the role of Young Charlie opposite Judd Hirsch, Tony Shalhoub, and Jason Biggs (also making his Broadway debut). Soon after his run on Broadway, Krumholtz co-starred in two feature films, Life With Mikey (1993) opposite Michael J. Fox and Addams Family Values (1993) opposite Christina Ricci For his role in Mikey, David was nominated for a 1993 Young Artist Award. Although his work in these two films garnered him critical attention, David is probably best known by children and the young-at-heart as the sarcastic head elf Bernard from The Santa Clause (1994) and its 2002 sequel The Santa Clause 2: The Mrs. Clause, but for contractual disputes was unable to be a part of The Santa Clause 3: The Escape Clause.

In 1994, at age of sixteen, Krumholtz co-starred in his first television series, Monty, with Henry Winkler. The show only lasted a few episodes. Krumholtz would star in several short-lived series over the years. 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). In 2005, he finally found television success with the CBS series Numb3rs, now renewed for a fifth season. Along with his starring roles on television, Krumholtz made memorable guest appearances on ER, Law & Order, Undeclared, Lucky, and Freaks and Geeks.

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 Arkinand Natasha Lyonne. In 1999, David starred as Michael Eckman in the popular teen movie 10 Things I Hate about You with Joseph Gordon-Levitt, Julia Stiles and Heath Ledger That same year, he portrayed a completely different teen character - that of Yussel, a young conflicted Jewish man in Liberty Heights.

It was the role of Yussel that brought Krumholtz to the attention of actor and filmmaker Edward Burns, who cast him in the 2001 independent movie Sidewalks of New York. Playing the romantic and slightly obsessed Benny, Krumholtz was on a path to larger, more complex film roles. His first role as a leading man was in the 2002 romantic comedy You Stupid Man, playing opposite Milla Jovovich Krumholtz carried his first leading role in a released American film when he starred Big Shot: Confessions of a Campus Bookie, which premiered on FX Networks in 2002.

In 2004, Krumholtz reunited with Edward Burns for the independent film The Last Hold-Outs. The following year he played Max in My Suicidal Sweetheart (formerly Max and Grace), once again starring opposite actress Natasha Lyonne. Krumholtz also returned to smaller key roles in the successful films Ray and Harold and Kumar Go to White Castle - two very different movies released in 2004. In September 2005, he was seen in Joss Whedon's science fiction film Serenity as Mr. Universe.

On Numb3rs, he plays the part of Charlie Eppes, a mathematical genius who helps his brother Don (Rob Morrow, an FBI agent, solve crimes using mathematics. The cast of Numb3rs also includes Judd Hirsch, who gave David his start in acting back in 1992 on the Broadway stage, and Peter MacNicol, who appeared with him in Addams Family Values as a camp counselor. Television critic Matt Roush called Krumholtz's work on Numb3rs "probably his best TV work to date".