Roberto Duran later fought for the World Middleweight Championship, meeting Marvelous Marvin Hagler in Las Vegas on November 10, 1983. During the fight, Duran broke his hand and lost in a very competitive fight that went the full fifteen rounds. After 13 rounds, two of the judges had Duran one point ahead, and the other judge had it even. Hagler fought tenaciously to win the final two rounds and get a unanimous decision victory. The judges' scores were 144-142, 114-143, and 146-145. Despite the loss, Duran became the second man to take Hagler to a fifteen round decision (Vito Antuofermo was the other) and the only one to do so while Hagler was the world champion.

In June 1984, Duran was stripped of his Light Middleweight title when the WB did not approve of his fight with WBC Champion Thomas "Hitman" Hearns and took away recognition of Duran as world champion the moment Duran stepped into the ring to box Hearns. Duran again made history in the fight, but this time it was the wrong kind. Hearns dropped Duran twice in the first round and as he rose to his feet after the second knockdown, which ended the round, the former champion did not know where his corner was. Hearns went on to knock Duran down a third time in the second round and the fight was stopped, marking the first time in his career that Duran had been knocked out in a fight (the "No Mas" fight was officially recorded as a technical knockout, because Duran quit). Duran then retired for a second time, but changed his mind over a year later, and was back fighting in early 1986.

Roberto Duran did not contend another title fight until 1989, but made the shot count when he won the WBC Middleweight title from Iran Barkley in February. The fight is considered one of Duran's greatest achievements, as the 37 year old former lightweight champion took the middleweight crown, his fourth title. In a tough back and forth fight, Duran knocked Barkley down in the eleventh round and Duran won a split decision (118-112, 116-112, 113,116). The bout was named the 1989 "Fight of the Year" by The Ring.

Super middleweight

Duran moved up to super middleweight for a third fight with Sugar Ray Leonard in December 1989 (a fight dubbed Uno Mas, One More, by promoters), where Leonard's WBC super middleweight title was on the line, although Leonard's camp insisted that the fight with Duran be at a 162lbs super middleweight limit that Duran favoured. In the end, both weighed in below the 160lbs middleweight limit. Duran was uncharacteristically flat for most of what was a strange fight. Although Leonard won the fight by a wide unanimous decision (1200-110, 119-109, 116-111), by the end of the fight Leonard looked the worse for wear as he had suffered several bad cuts. Leonard's lip was bused by a headbutt in the fourth round, his left eye was cut in the eleventh round and his right eye was cut in the twelfth round. The cuts required more than 60 stitches. Duran didn't fight again until 1991, so had given up his WBC middleweight crown that he had won against Barkley. Duran seemed to be in decline after the third fight against Leonard, but he persisted and worked his way into title shots for the lesser IBC super middleweight and middleweight titles in 1994, 1995 and 1996.

Duran fought Vinny Pazienza twice, in June 1994 and January 1995, for the IBC Super Middleweight Championship, with Pazienza winning both times by unanimous decision. In the first fight, Duran put Pazienza down in Rounds 2 and , but referee Joe Cortez controversially ruled the Round 2 knockdown to be a slip. The first fight divided the people watching as some felt that Duran had won a close fight, but others felt that Pazienza had won either narrowly or widely after finishing strongly in the last five rounds. The second fight was more lopsided in Pazienza's favour, as despite the official judges giving Pazienza the win by scores of 115-112, 117-111 and 118-110, the TV commentators expressed puzzlement at the closeness of the official scoring as they though that Pazienza had won every round in a 120-108 shutout.

In 1996, Duran fought Hector Camacho for the vacant IBC Middleweight Championship. At the end of the fight, fans and TV commentators seemed in complete agreement that Duran had won the fight in an excellent performance, but the three judges saw the fight very differently and awarded Camacho the victory by a very controversial unanimous decision. Duran's old rival, sugar Ray Leonard, commentating at ringside, was baffled at the scoring and called it an early Christmas gift for Camacho, with the result motivating Leonard enough to come out of a 6 year boxing retirement to face Camacho himself in 1997.