Grigolo was born in Arezzo and, while still young, moved to Rome, where his talents were noticed at an early age. When he was nine years old he accompanied his mother to have her eyes tested and, hearing someone singing from another room, he spontaneously began his own rendition of "Ave Maria." The singer, the optician's father, was so impressed that he insisted Grigolo have an audition for the Sistine Chapel Choir as soon as possible.

The young tenor joined the choir and became a soloist. At age 13 he played the Pastorello in a performance of Tosca at Rome's opera house, where he shared the stage with Pavarotti. By 18 he was singing with the Vienna Opera Company and, at 23, he was the youngest man to perform in Milan's La Scala. He was also the first Italian man to be excused from compulsory military service for fear of interrupting his career.

Grigolo sang in performances of the Barber of Seville, La Traviata, Così Fan Tutte, Faust, and many others before taking a life-changing role as Tony in West Side Story. Sharing the stage with James Gandolfini, he saw the potential of opera to reach a wider audience. After almost becoming a member of Il Divo, abandoned after clashes with Simon Cowell, he recorded a solo album, In the Hands of Love, in the genre he calls "popera." It features the song "Maria" from West Side Story as well as pop songs like "All in Love Is Fair" and "Bedshaped." The Classical Advisory Panel of England kept the album out of the classical charts, defining it as precisely 35.7 percent classical (a minimum of 60 percent is required for entry in the classical charts). In the Hands of Love debuted in the Top Ten of the U.K. pop charts instead.