Discovered in Rome by two Neapolitan producers, Antonio Ferrigno and Ettore Pesce, she debuted in La corda d'acciaio (The Steel Rope, 1953).

Initially, she appeared in musical films like E Napoli canta (Naples Sings, 1953) and Questa è la vita (Of Life and Love, 1954, with Totò).

In the late 1950s, Lisi performed on stage at Piccolo Teatro di Milano in I giacobini by Federico Zardi under the direction of Giorgio Strehler.

Lisi also promoted a toothpaste brand on television with a slogan that would become a catchphrase among Italians: "con quella bocca può dire ciò che vuole" (with such a mouth, she can say whatever she wants).

Lisi then starred with Frank Sinatra, in Assault on a Queen (1966), in The Girl and the General, co-starring with Rod Steiger, and in two films with Anthony Quinn, The Secret of Santa Vittoria, directed by Stanley Kramer, and the war drama The 25th Hour.

To overcome her typecasting playing seductresses, Lisi sought new types of roles, of evil women or of a lover in relationships of disparate age for example.

[4] Lisi also starred in The Birds, the Bees and the Italians (1966) which shared the Grand Prix (then equivalent to the Palme d'Or, which was not awarded at the time) with A Man and a Woman at the Cannes Film Festival that year.