She had her break into films after winning a Tunisian beauty contest in 1957. She made her film debut in Goha (1958) and later that year had a role in the minor international success I Soliti ignoti. Her early career was largely managed by producer Franco Cristaldi. Throughout the 1960s she appeared in many Italian or Italian co-financed films including Luchino Visconti's Il Gattopardo (The Leopard, 1963), Rocco e i suoi fratelli (1963), Federico Fellini's 8 1/2 and Sergio Leone's epic Once Upon a Time in the West (1968). She attempted to break into the US market but was let down by her poor command of English, although she learnt French and Spanish with little difficulty. Her Hollywood films include Circus World (1964), The Pink Panther (1964) and The Hell With Heroes (1968).
Cardinale remains active in European cinema, her later films include Qui comincia l'avventura (1975), Fitzcarraldo (1982), La Storia (1985) and Un homme amoureux (1987)
She has been married twice, to Squitieri and then Franco Cristaldi, and has two children.