Mark Herzlich played college football at Boston College University  where he earned College Football News Freshman All-American honors. As a sophomore he started all 14 games for the Eagles. Herzlich entered his junior season (2008) as a preseason all-star candidate. He was named to the Lott Trophy and Butkus Award watchlists prior to the season. In 2008 Herzlich was a First-team All-American and the ACC Defensive Player of the Year. He was also a finalist for the Butkus Award, and a quarterfinalist for the Lott Trophy. In November 2008, Herzlich was a projected top-15 pick by many scouts for the 2009 NFL Draft but announced his return to Boston College for the 2009 season.

Herzlich missed the entire 2009 season due to Ewing's Sarcoma, a rare form of bone cancer, which he overcame and earned numerous honors for his courage and outreach, including the Disney Spirit Award, Nils V. "Swede" Nelson Award, an honorary Lott Trophy, and the ACC Commissioner’s Cup.

In 2010 Herzlich returned to the football field and won the Rudy Award and the ACC's Brian Piccolo Award after starting all 13 games and finishing third on the team with 65 tackles and 50 solo stops.

Herzlich was not selected in the 2011 NFL Draft even though he was invited to attend the event. On July 26, 2011, Herzlich signed as an undrafted free agent with the New York Giants. Herzlich made the New York Giants final 53 man roster. On November 20, 2011, Herzlich made his first NFL start against the Philadelphia Eagles.