Guido is the son of the late cardiologist Massimo Calabresi and European literature scholar Bianca Maria Finzi-Contini Calabresi (1902 - 1982). Calabresi's parents, active in the resistance against Italian fascism, eventually fled Milan for New Haven, Connecticut, immigrating to the United States in September 1939. The family became naturalized American citizens in 1948. Guido's older brother Paul Calabresi (1930 - 2003) was a prominent medical and pharmacological researcher of cancer and oncology.

Calabresi married Anne Gordon Audubon Tyler, a social anthropologist, freelance writer, social activist, philanthropist and arts patron. Both received their primary education at the Foote School in New Haven, graduating in 1946 and 1948, respectively. They reside in Woodbridge, Connecticut and have three children. Anne Gordon Audubon Calabresi (Anne Calabresi Oldshue), a psychiatrist, graduated cum laude from Yale, attended medical school at Case Western Reserve University and completed residency at Harvard. Massimo Franklin Tyler ("M.F.T.") Calabresi, a journalist, also graduated from Yale. Bianca Finzi-Contini Calabresi attended Yale as well, graduating summa cum laude, and has a Ph.D. in Renaissance literature from Columbia.

Calabresi's nephew, Steven G. Calabresi, is a renowned Constitutional Law professor at Northwestern University. After graduating cum laude from Yale University, he attended Yale Law School, where he was editor of the Yale Law Journal, and went on to clerk for The Hon. Robert Bork on the D.C. Circuit and Justice Antonin Scalia on the United States Supreme Court.

Calabresi received his B.S. summa cum laude from Yale College in 1953, majoring in economics --a choice which would have significant connections with his later pursuits. He was then selected as a Rhodes Scholar, studying at Magdalen College, Oxford, which awarded him a B.A. with First Class Honors in 1955. He received his law degree (LL.B.) magna cum laude from Yale Law School in 1958, graduating first in his class, and was also a law review member as Note Editor of the Yale Law Journal from 1957 to 1958. Following graduation from Yale Law, Calabresi served as a law clerk for U.S. Supreme Court Associate Justice Hugo Black from 1958 to 1959. Additionally, he earned a M.A. in politics, philosophy, and economics from the University of Oxford in 1959; and is a member of Phi Beta Kappa and the Order of the Coif.

Calabresi joined the faculty of the Yale Law School upon completion of his Supreme Court clerkship, becoming the youngest ever full professor at Yale Law, and was Dean from 1985 to 1994. He now is Sterling Professor Emeritus of Law and Professorial Lecturer in Law at Yale.

Calabresi is a member of the Connecticut Bar and from 1971 to 1975 served as town selectman for Woodbridge, Connecticut.

Calabresi is, along with Ronald Coase, a founder of law and economics. His pioneering contributions to the field include the application of economic reasoning to tort law, and a legal interpretation of the Coase theorem. Under Calabresi's intellectual and administrative leadership, Yale Law School became a leading center for legal scholarship imbued with economics and other social sciences. Calabresi has been awarded more than forty honorary degrees from universities across the world. He is a member of the Royal Swedish Academy of Sciences.

On February 9, 1994, President Bill Clinton nominated Calabresi as circuit judge to the U.S. Court of Appeals for the Second Circuit, he was confirmed by the United States Senate on July 18, received his commission on July 12, and entering duty on September 16, 1994, replacing Thomas Joseph Meskill. President Clinton is a 1973 graduate of the Yale Law School, although he never had Calabresi as a professor. Among Calabresi's expansive group of former students are Supreme Court Justices Samuel Alito, Clarence Thomas and Sonia Sotomayor, former United States Attorney General Michael Mukasey, feminist legal scholar and law professor at the Universities of Michigan and Chicago Catharine MacKinnon, former White House Counsel Gregory Craig, Senator John Danforth, Harvard Law School professor Richard H. Fallon, Jr., civil and human rights legal scholar Kenji Yoshino, and noted torts scholar and law professor at the University of Virginia Kenneth Abraham.

Calabresi took senior status on July 21, 2009.

Yale, in 2006, created the Guido Calabresi Professorship of Law, with Kenji Yoshino serving as the inaugural professor of the endowed chair.

Calabresi is the author of four books and over 100 articles on law and related subjects.