Nicholas is known for his roles in Rookie of the Year (1993) and American Pie (1999). He appeared in the four theatrical films of the American Pie franchise, as the character Kevin Myers, played Frank Sinatra, Jr. in the Showtime movie Stealing Sinatra, and co-starred in Halloween: Resurrection. In 2009, he played the role of a rookie cop in the drama Life Is Hot in Cracktown. He played Eugene in Nicole Holofcener's Please Give, which won the 2011 Indie Spirit Robert Altman Award. He had the role of Abbie Hoffman in the film entitled The Chicago 8. He also appeared on an episode of ABC's Grey's Anatomy as Jeremiah. "I started acting when I was 6 years old. I have always enjoyed making people laugh or smile or think," he says.

Nicholas married Colette Marino, known as DJ Colette, in 2007. The couple had their first child, a boy named Nolan River, in 2011. Their second child, a girl named Zoë Dylan, was born in April 2016.

Nicholas released his debut album, Without Warning, on January 15, 2008, and his follow-up album, "Without Warning Acoustic" on February 28, 2009. Heroes Are Human, on June 1, 2010. His fourth release is a self-titled EP, released March 20, 2012, in which the first single "My Generation" is also on the American Reunion Soundtrack album. His fifth release is the EP Security released on April 8, 2014.

On June 30, 2010, Nicholas threw out the first pitch at the Chicago Cubs game at Wrigley Field and sang the seventh-inning stretch. He was invited back to sing the anthem on July 7, 2015 for the second game of a doubleheader against the St. Louis Cardinals. Following the Cubs' win over the Indians in Game 7 of the 2016 World Series, Nicholas, in celebration, tweeted the final shot from Rookie of the Year: Henry holding his fist up to the camera to show a Cubs World Series ring.

In March 2015, Nicholas appeared on Blues Traveler's album Blow Up the Moon, co writing the song "All the Way."