Andruzzi played college football at Southern Connecticut State University in New Haven, Connecticut, where he majored in special education. He played every position on the offensive line and started all four years. Andruzzi was a Division IIAll-American his junior and senior years as well as an offensive team captain during his senior season. Andruzzi played high school football at Tottenville High School in his hometown of Staten Island, New York City, New York. He was a classmate of Major League baseball All Star starting pitcher Jason Marquis and a teammate of Adewale Ogunleye, defensive end for the Miami Dolphins and then the Chicago Bears.
In 1997, Andruzzi was picked up as an undrafted rookie free agent by the Green Bay Packers. He was allocated by the Packers in February 1998 to play football in Scotland for NFL Europe. Andruzzi was released from the Packers after three seasons. He was then signed by the New England Patriots in 2000, where he played five seasons and earned three Super Bowl rings. In recognition of his contributions, Andruzzi received the Ed Block Courage Award in 2002 and the first Ron Burton Community Service Award in 2003. Andruzzi became a free agent in February 2005 and was signed by the Cleveland Browns. He played with them for two seasons.
In 2001, Andruzzi and his wife, Jen, were introduced to C.J. Buckley, who had an inoperable brain tumor. The families became very close and, therefore, it was devastating when C.J. died late in 2002. Always driven to help others in need, the couple launched the C.J. Buckley Brain Cancer Research Fund at Children's Hospital.
On May 30, 2007, Andruzzi was diagnosed with non-Hodgkin's Burkitt's lymphoma, predicted to double in size in just 24 hours. The family relocated back to New England where Andruzzi had an aggressive form of chemotherapy treatment over three months at Dana-Farber Cancer Institute and Brigham and Women's Hospital. Andruzzi's last treatment was on August 6, 2007 after which he spent the following year at home in recovery.
After completing treatment, the Andruzzi family founded the Joe Andruzzi Foundation in 2008. They are committed to tackling cancer's impact by providing financial assistance for patients and their families as well as funding pediatric brain cancer research.
Andruzzi has three brothers. All three are members of the New York City Fire Department, and responded to the attacks on the World Trade Center on September 11, 2001. During pregame introductions at the next game on September 23, Andruzzi ran out with an American flag in each hand. His brothers were honored at midfield prior to kickoff.
On April 15, 2013, Andruzzi's foundation was hosting an event at a business on Boylston Street in Boston when the 2013 Boston Marathon bombings occurred. In the aftermath, he was photographed carrying an injured woman. Andruzzi's friend, former Patriots linebacker Matt Chatham, was also present, and uninjured.