For the 2015 season, Iannone replaced Cal Crutchlow at Ducati Corse, and partners Andrea Dovizioso in the team. Iannone achieved his first MotoGP podium on his Ducati début, finishing third in Qatar. At Austin, he finished in fifth place behind Jorge Lorenzo, and also recorded the first fastest lap of his MotoGP career. Iannone was on course for a second podium in Argentina, but was passed for third on the final lap, by Crutchlow. At Phillip Island Iannone was involved in a lengthy four-way battle for first with three former world champions Lorenzo, Marc Márquez, and Valentino Rossi. He finished third after overtaking Rossi on the final lap with three corners remaining.
He began his 2016 season well, leading at Losail for 6 laps before low-siding, allowing his teammate to overtake. The following Grand Prix in Argentina saw Iannone in 3rd before attempting a last lap overtake of his teammate Dovizioso, resulting in both riders falling. Iannone was penalised by Race Direction with a penalty point and three places on his following starting grid placement. Despite these punishments Iannone finished his first race of the season on the podium with a 3rd place behind Marc Márquez and Jorge Lorenzo, ending his season-spanning four race long run of race retirements. He raced aggressively at Catalunya, and eliminated Lorenzo from 5th place, effectively giving Marquez the championship lead.