Greenfield was born and raised in Dobbs Ferry, New York. He is Jewish and had a Saturday Night Live-themed Bar Mitzvah. As of 2011, he lives in Los Angeles, California with his wife, Tess Sanchez (a casting director). The couple has one child.
Greenfield began pursuing his acting career in 1998 after he graduated from high school. He landed guest stints on dramas such as Boston Public, Gilmore Girls and The O.C. Greenfield scored his first lead role on the short-lived series Modern Menas one of three bachelors who hire a life coach to help them understand and manage women. Greenfield had more success in supporting roles on Veronica Mars (reprising the role in the film adaptation in 2014) and Greek.
In 2007, he landed a recurring role on Ugly Betty. He continued his television career with a slew of guest starring roles on primetime series such as The CW's remake of Melrose Place, the short-lived No Ordinary Family, and Castle.
He created, produced and starred in the comedy series The Gentlemen's League for the Audience Network in 2010, which followed the real-life fantasy football league he ran with actor Jerry Ferrara. As for film, Greenfield had his feature film debut in the Cross Bronx. Greenfield had a featured role in When Do We Eat?, as an Internettycoon who, after losing his fortune, becomes a Hasidic Jew.
In 2011, Greenfield began playing the role of Schmidt in the sitcom New Girl alongside Zooey Deschanel. The role earned him nominations for both a Primetime Emmy Award for Outstanding Supporting Actor in a Comedy Series and a Golden Globe Award for Best Supporting Actor – Series, Miniseries or Television Film.