Born in Omaha, Nebraska to a pair of psychologists and raised in one of the few Jewish families in the region, Greenberg grew up in a Conservative household, belonged to Jewish youth groups, went to Jewish summer camps and traveled to Israel. His family moved to St. Louis when he was 12 and he subsequently majored in acting while earning a B.F.A. at New York University, appearing in stage productions while at NYU, then went on to perform with several other theater companies while sporadically appearing in TV and commercial roles. Greenberg made his small screen debut with a 1997 guest appearance on "Law & Order" and made his big screen debut the following year in "A Civil Action" (1998), starring John Travolta.
In 2000, Greenberg's career began to heat up with guest appearances on "The Sopranos" (1999), "Third Watch" (1999), and "Boston Public" (2000). He landed a lead role in 2002 as a teenager in the big budget feature "The Perfect Score" (2004), co-starring alongside Erika Christensen and Scarlett Johansson, then got a recurring role as Jake on The WB series "One Tree Hill" (2003 - ), in a recurring role as high school basketball player Jake Jaglieski, who leads a double life as a single father. He was then tapped by executive producers George Clooney and Steven Soderbergh to be one of the three principals on their unique HBO series "Unscripted" (2005). Playing a variation of himself (with the same name and TV credits) in the improvised series based on the actors' true Hollywood experiences, Greenberg showed the ups and downs of a performer's life alongside fellow thespians Krista Allen and Jennifer Hall--in one scene, Greenberg accidentally offends actor Noah Wylie by not recognizing him while guest-starring on an episode of "ER"; in another, a casting director catches him in a lie after padding his acting resume. Through the course of the one-season series, "Unscripted" even incorporated Greenberg's real-life casting opposite Uma Thurman and Meryl Streep in the comedy "Prime" (2005) into its storyline, including Greenberg's conversations with both actors, and later in the year the film hit theaters, with Greenberg playing the much younger lover of a woman (Thurman) who also happend to be the patient of his therapist mother (Streep).
An accomplished singer and musician, Greenberg has performed an original song on an episode of "One Tree Hill."