He founded the B. Thomas Golisano Foundation in 1985 with an initial gift of $90,000. The Foundation awards grants to organizations dedicated to providing opportunities for those with intellectual and developmental disabilities and their families. The Foundation has assets exceeding $32 million and awards about $2 million in grants annually to organizations primarily in western and upstate New York and Florida. Golisano's personal and foundation philanthropy to health care, education, and other organizations now totals more than $267 million. There are three children's hospitals named for him. (Rochester, NY, Syracuse, NY and Fort Myers, Florida)

In February 2001 Golisano donated $14 million to the Rochester Institute of Technology for the B. Thomas Golisano College of Computing and Information Sciences. He donated an additional $10 million to RIT for the new Golisano Institute for Sustainability there in 2007.

Golisano donated $14 million to the University of Rochester, which renamed their pediatric facility at Strong Memorial Hospital in his honor as the Golisano Children's Hospital in 2002. In 2012 Golisano pledged an additional $20 million to URMC to build a new Golisano Children's Hospital, which opened in 2015.

In 2003, Golisano was awarded the first-ever Humanitarian Award by the Italian-American Community Center in Rochester.

Golisano was a founding sponsor of the Clinton Global Initiative and was an underwriter of CGI's annual meeting for nine years from 2005 through 2013.In 2005 Golisano contributed $6 million to the Upstate University Hospital in Syracuse for a new children's hospital. The hospital was named Upstate Golisano Children's Hospital in his honor.

In October 2003, Golisano donated $5 million to Nazareth College, which named the new Golisano Academic Center in his honor. In July 2004, he made a $5 million gift to Hartwick College of Oneonta, New York, which was used to build a new academic building for the social science and management programs, and has been named Golisano Hall. On March 6, 2006, Golisano donated $6 million to Bishop Kearney High School and Our Lady of Mercy High School.

On October 8, 2008, Golisano donated $10 million to Niagara University for a new B. Thomas Golisano Center for Integrated Sciences building that was named in his honor.

In November 2009, Golisano donated $4 million to Ave Maria University for the construction of a new field house.

In February 2011, Golisano became the spokesman for National Popular Vote Inc., a non-profit organization seeking to implement a popular vote system for presidential elections by harnessing the electoral college.

Also on 2012, Golisano donated $20 million in 2012 to build a new Golisano Children's Hospital at Lee Health in southwest Florida. The new hospital will open in Spring 2017.

Three times divorced, Golisano is married to former tennis star Monica Seles. The two announced their engagement on June 5, 2014.

Tom Golisano and the Golisano Foundation were recognized among 30 great givers and causes on Forbes' "Philanthropy's Big Bets for Social Change of 2015."

In June 2016, the new Golisano Center for Community Health opened its doors to patients. The center, which provides comprehensive integrated health care to people with disabilities and their families, was made possible with a gift of $3.5 million from Golisano.

In 2017, in Austria, at the Special Olympics World Games, the first Golisano Global Health Care Leadership Award s will be announced and presented to recognize those who are advancing inclusive health for people around the world with intellectual disabilities.