However, Allman's playing had impressed Rick Hall, owner of the renowned Fame studio, who booked the young musician for a forthcoming session with soul singer Wilson Pickett. The resultant album, Hey Jude (1968), was both a commercial and artistic success, and Allman was invited to join the studio's in-house team.

The guitarist made several distinctive appearances over the ensuing months. He was featured on releases by Aretha Franklin, King Curtis, Clarence Carter, Otis Rush and Boz Scaggs, but grew frustrated with this limiting role. The time in Muscle Shoals was not a waste, however, as Duane had rented a small cabin well out of town on a lake, and spent many hours there by himself, refining his playing, and adding electric slide guitar to his repertoire. During one of his periodic visits back home to Florida, he joined a group of local musicians which became the Allman Brothers Band with the addition of younger brother Gregg.

A gig in Miami gave Duane the chance to participate in one of the greatest of all rock and roll albums, Layla and Other Assorted Love Songs. Eric Clapton had long wanted to meet Duane after hearing his work on Hey Jude. When he heard that the Allman Brothers were due to play in Miami, where he had just started work on Layla, he insisted on going to see their show. He was allowed to sit at the front of the stage, and made his way out while Duane had his eyes closed, playing a solo. His shock when he opened them, to see the great Eric Clapton sitting at his feet, was substantial! After the show, the two returned to the studio, and hit it off immediately to an amazing degree, with the result that Duane wound up participating in most of the tracks on Layla, contributing some of his best slide guitar work.

Allman then returned to the Allman Brothers band, despite being offered a permanent position with Clapton, and went on to record the classic Live at Fillmore East with them, another of the classic albums of rock and roll. In the summer of 1971, the Allman Brothers began work on their fourth album, Eat A Peach, in Macon, Georgia. Tired from constant touring, they took a break mid-way though the sessions. It was during this break that Duane Allman died. On 29 October, he was out for a ride on his Harley-Davidson, when, in an effort to avoid a collision with a log truck, he lost control of his bike and struck his head; he died following three hours of intensive surgery. Allman was 24.