He graduated from Thomas Jefferson High School and earned a bachelor's degree from Brooklyn College in 1980 and an MFA from Cornell University in 1982.

One of Smits's most acclaimed roles was that of Detective Bobby Simone on the ABC television program NYPD Blue, in which he starred from 1994 to 1998.

Smits played the role of Congressman Matt Santos of Houston, Texas, in the final two seasons of the NBC television drama The West Wing,[13] joining fellow L.A. Law alumnus John Spencer.

In Dexter season 3, Smits played the role of Miguel Prado, an assistant district attorney who befriends the title character.

Additionally, Smits portrayed the character Alex Vega in the CBS TV series Cane, which aired from September 25, 2007, to December 18, 2007, and was subsequently canceled by the network due to the 2007 Screen Writer's Guild strike.

Smits joined the Sons of Anarchy cast in season 5 as Nero Padilla, a high-level pimp who refers to himself as a "companionator".

[18] Bluff City Law brings Smits back to TV courtrooms on a steady basis for the first time in over a quarter century since his role in L.A.

Smits has participated in the Public Theater's New York Shakespeare Festival, playing the role of Duke Orsino in Twelfth Night in 2002 and Benedick in Much Ado about Nothing in 2004.

In 2003, Smits starred in the Broadway production of the Pulitzer Prize-winning play, Anna in the Tropics, by Nilo Cruz, performed at the Royale Theatre.

From November 2009 to February 2010, he appeared opposite Christine Lahti, Annie Potts, and Ken Stott in the critically lauded Broadway play God of Carnage, replacing Jeff Daniels.

[21] Throughout his career on television, he has garnered eleven Screen Actors Guild Awards nominations, winning once in the Outstanding Performance by an Ensemble in a Drama Series in 1995 for NYPD Blue.

He also received the Ackerman Leadership Award for his work "championing bilingual and bicultural mental health and social services for Latino families.

[25][26] Smits helped found the National Hispanic Foundation for the Arts[27][28] to advance the presence of Latinos in the media, telecommunications, and entertainment industries.