Frankie Valli scored over 25 Top-40 hits with The Four Seasons, a handful of Top-40 hits dubbed as a solo act in the late 1960s, one dubbed as The Wonder Who? in 1965, and again in the mid to late 1970s. His best known "solo" single is Can't Take My Eyes Off You. He was inducted into the Rock and Roll Hall of Fame along with The Four Seasons in 1990.

Valli started his singing career in 1952. He cut his first single in 1953 as "Frankie Valley," a name he adopted from Jean Valley, his favorite female singer. In the mid-1950s he split up with the Travellers and joined The Variety Trio, which consisted of Tommy DeVito, twin brother Nick, and Hank Majewski. They redubbed themselves the Variatones, and later, "The Four Lovers" and had a top 40 hit with "Apple of My Eye" in 1956. After a few more name changes, the group was renamed "The Four Seasons" in 1960. About the same time, Valli Italianized his name to its current form. Nick DeVito and Majewski left the group in 1960 or 1961 and were replaced by Bob Gaudio and Nick Massi. As the lead singer of the Four Seasons, he had a string of hits beginning with a #1 hit "Sherry" in 1962. Valli has been the lead singer from then until the present time, occasionally releasing singles under his own name, notably the theme song from the film version of Grease, written by Barry Gibb, which was a #1 hit.

Valli is best remembered for his falsetto vocals, once prompting comedian Jackie Mason, referring to Walk Like A Man, to exclaim, "Sing like a man, Frankie!" Another singer who has been compared with Valli is Lou Christie.

He has made several appearances on the hit series The Sopranos as New York mob captain Rusty Millio. Ironically, Valli himself was referenced earlier in the series. In the Season Four episode, "Christopher," the owner of a Native American casino offers Tony Soprano his help in getting a local Indian organization to drop its planned anti-Columbus Day demonstration. In exchange, Tony is asked to get Frankie Valli to agree to perform at the casino.

John Lloyd Young won the 2006 Tony Award for Best Leading Actor in a Musical for his portrayal of Valli in the musical Jersey Boys. After the great success of the musical on Broadway, it has been reported that Valli is excited at the prospects for bringing the show to Las Vegas.