Born in Vasto, Province of Chieti, Iannone started his career on pocket bikes and soon became a championship front runner. He participated in both the Italian and Spanish championships before moving to World Championship in 2005. On 4 May 2008, Iannone claimed his first win at the Chinese Grand Prix in Shanghai, in wet conditions. Prior to the victory, he had never finished higher than ninth, at the Turkish and French Grands Prix in 2007, although he had previously qualified as high as seventh. In the 2009 125 cc season he won the first two races of the season, establishing himself as a championship contender, however he faded to seventh overall, with only one more win. During the race at Misano, Iannone provoked an accident with Pol Espargaró. After the incident, images showed the riders arguing in the gravel and Iannone headbutted Espargaró. This was heavily criticised by the media and lost Iannone some sponsorship; Iannone then apologised to Espargaró at the next race at Estoril.

In 2010, Iannone moved up to the new Moto2 series, his first time riding anything other than an Aprilia. After a slow start he took victories at Mugello and Assen – both from pole – making him the first rider to take two poles in the class, to move up to fourth overall in the standings. He was also competitive in Barcelona, but received a ride-through penalty for overtaking Yuki Takahashi under yellow flag conditions. He then went on to win again at Motorland Aragón, a track which was new to the MotoGP calendar in 2010.

2011 proved to be a very up and down season for Iannone, with inconsistency being his major downfall. Whilst being the only other rider besides Stefan Bradl and Marc Marquez to win more than one race, he would often find himself qualifying well outside the top 10, but finished the season in third place after beating Alex de Angelis in the final race of the season in Valencia. On the Tuesday following the race, Iannone tested a MotoGP bike for Gresini Racing in Valencia.

Iannone remained in the class for the 2012 season, finishing second in the season-opening Qatar Grand Prix, having led the race out of the final corner and losing out to the straight line speed of Marc Marquez's bike. He finished fourteenth, fifth and fourth over the next three races, before taking his first victory of the season in the Catalan Grand Prix. He went on to get another podium at Assen. After this, he won his home race at Mugello wearing the colours of a nearby fire station.

In 2013, after another third place in the Moto2 championship, Iannone moved up into MotoGP on a Ducati Desmosedici with Pramac Racing. He finished the season in twelfth place with five top-ten finishes. His best result was an eighth place at the Australian Grand Prix at Phillip Island, but the second part of his season was affected by a shoulder injury suffered during free practice at the German Grand Prix. The injury also forced him to miss the United States Grand Prix at Laguna Seca.

In 2014 he continued to race with Pramac Racing, with teammate Yonny Hernández.

For the 2015 season, Iannone replaced Cal Crutchlow at Ducati Corse, and partnered Andrea Iannone. 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 Marquez, and Valentino Rossi. He finished third after overtaking Rossi on the final lap with three corners remaining.

Ducati kept their line up for 2016 and he began the 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 grid places at the next round in Austin. Despite these punishments, Iannone finished his first race of the season on the podium with 3rd place, behind winner Marc Marquez and Jorge Lorenzo, ending his run of four consecutive race retirements starting at the previous years Malaysian Grand Prix. He scored points Spain, retired in France and then got the fastest lap on route to 3rd at his home race at Mugello. He raced aggressively at Catalunya, and eliminated Lorenzo from 5th place, giving winner Marquez a 10 point championship lead.

Iannone scored points at the Dutch TT and Germany and then at Austria came his best race weekend of the season and of his career so far. His pace was evident throughout the weekend as he finished in the top two of every session apart from the first practice session, in which he was third. He started the race from pole position and although he briefly lost the lead at the end of lap one, he regained it before his teammate took it from him and led between laps 10 and 20. Iannone took the lead again and led until the finish winning from his teammate by 0.938 seconds whilst also claiming another fastest lap. It was Ducati's first MotoGP win since 2010 and Iannone's first MotoGP win, and to date is his only win. He finished 8th in Brno and then came the British round of the championship. At Silverstone, he qualified on the third row in 8th place and fought his way through the field. Around the halfway mark of the race, he began to have fatigue in his right forearm which made the bike difficult to control. He arrived at turn 17 on lap 14, turned late, hit a bump, and crashed out.

At the San Marino Grand Prix, Iannone had a low-side crash at the fast turn 15, he appeared unharmed but checks revealed he had fractured his T3 vertebrae which ruled him out of the rest of the weekend. He took part in practice 1 at the following race two weeks later in Aragon after being cleared to race, but was still having pain so decided to withdraw from the race weekend. He still wasn't 100% Fit to race in both Japan and Australia. In total he missed four races and returned in Malaysia where he crashed out from 3rd on lap 12. It was the fourth time he had retired from a podium position in 2016. He finished the year strongly with a podium in his final race for Ducati. He showed pace throughout the season but lacked consistency and even with missing four races, he finished 9th in standings with 112 points.

On May 19, 2016, Team Suzuki Ecstar announced that Iannone had signed with the outfit for 2 seasons as a factory rider. Iannone paired at Suzuki with MotoGP rookie Álex Rins.

In 2018 ahead of his home Italian Grand Prix, Iannone announced that he and Suzuki would part ways at the end of the season.

During the 2018 season, Iannone signed with the Aprilia factory-supported Aprilia Racing Team Gresini on a 2-year deal partnering incumbent rider Aleix Espargaró.

In December 2019, Iannone was provisionally suspended from motorcycle racing after a positive drug test.