Grimaldi came from a family of dancers and entertainers and made his debut as a dancer at age four at the Sadler's Wells Theatre. For a number of years he appeared at two theatres nightly, running from one to the other. In 1806 he joined Covent Garden Theatre, where, in the pantomime Harlequin Mother Goose, he enjoyed his greatest success. In this production he created a new type of clown combining rogue and simpleton, criminal and innocent dupe in one character, a role subsequently adopted by many other English clowns. His whiteface makeup and impudent thievery became the norm for all pantomime clowns (“Joeys”) who came after.

In 1816 Grimaldi terminated his relationship with the Sadler's Wells Theatre but two years later purchased a part interest in it. In 1822 his health began to fail and he was unable to fulfill his remaining commitments at Covent Garden. He was made assistant manager at Sadler's Wells in 1825 and gave his last public performance in 1828. At the height of his powers, Grimaldi was considered to have no equal as a comedic performer. His memoirs were edited by Charles Dickens in 1838.