Zeffirelli was born in 1923 in Florence, Italy. He began his career acting in the stage productions of Luchino Visconti; he also worked as an assistant on several Visconti-directed films. Following World War II Zeffirelli began designing opera sets and costumes while also working as an opera director. He directed a Swiss-produced film of La bohme in 1965.

Zeffirelli made his Metropolitan Opera debut in 1964 with his production of Falstaff. One of his most notable Met stagings was the world-premiere production of Samuel Barber's Antony and Cleopatra, which opened the new Metropolitan Opera House at Lincoln Center in 1966; Leontyne Price starred.

Zeffirelli sets have appeared frequently at the Met since. He was credited with production design of Cavalleria Rusticana and Pagliacci in 1970 and direction and set design of Otello in 1972, Tosca in 1985, La traviata in 1989, and Carmen in 1996.

His films include versions of several Shakespeare plays; including a 1967 Taming of the Shrew starring Richard Burton and Elizabeth Taylor.

Zeffirelli will be honored as part of the 2006 TDF/Irene Sharaff Awards for Theatrical Costume Design, named for the costume designer.