Piven's first significant role was as a regular castmember for several seasons on HBO's The Larry Sanders Show, where he played the headwriter Jerry. Piven has appeared in several successful films, including The Family Man, Black Hawk Down, Heat, PCU, Old School and Runaway Jury. He also had a brief cameo appearance as a gay salesman with a crush on Carter in Rush Hour 2.

Since 2004, Piven has played rambunctious Hollywood agent Ari Gold in the HBO series Entourage. He received Emmy nominations for best supporting actor three straight years from 2005 to 2007, and won the award in 2006 and 2007. Piven was also the star and producer of the short-lived ABC dramedy series Cupid, and was a supporting cast member on the last three seasons of the sitcom Ellen. He played the part of Ellen's cousin, Spence. He also voiced Elongated Man in three episodes of Justice League Unlimited.

In 2007, Piven appeared in the video for "Drivin' Me Wild", the third single taken from rapper Comm