Tucci made her Broadway debut in 1963, in The Milk Train Doesn't Stop Here Anymore. She has fourteen Broadway credits. Principal roles include Rose Delle Rose opposite Maureen Stapleton in the 1966 production of The Rose Tattoo by Tennessee Williams. In 1967, she starred as Alexandra Giddens in a revival of The Little Foxes by Lillian Hellman, with Anne Bancroft as her mother. In 1969, she was a replacement for Jane Alexander in The Great White Hope. In 1988, she starred in a revival of The Night of the Iguana as Hannah Jelkes. In 2009, she appeared in the production of Mary Stuart as Hanna.

Tucci began appearing in film in 1969. Her first credits were in Robert Frank's Me and My Brother and a CBS Playhouse production titled Shadow Game. She played Lisa in Sidney Lumet's 1983 film Daniel. In Gus Van Sant's 1995 film To Die For she portrayed Angela Maretto.

She was nominated for a Tony Award for Best Featured Actress in a Play in 1967 for her performance in The Rose Tattoo. She played Koula in the 2015 mini-series The Slap. She also won an OBIE award for her performance as Phaedo in "Talk" by Carl Hancock Rux at the Joseph Papp Public Theater.