2006 would be the greatest and most dramatic season of Hayden's career. Nicky started the season strongly, with seven podiums in the first eight races, including a win at Assen, which took him to the top of the riders' classification. This lead was then strengthened by a second win at Laguna Seca, putting him 34 points ahead of Dani Pedrosa and 51 ahead of Valentino Rossi.

However after the summer break momentum swung rapidly in favour of Rossi. Hayden slowly lost ground to the Italian, but was set to cling to the championship lead until a bungled pass by his own team-mate Dani Pedrosa took him out of the penultimate round in Estoril. Hayden's character shone through in the immediate aftermath and he soon focussed on trying to overturn Rossi's eight-point advantage at Valencia and become the first rider since 2000 to defeat The Doctor.

On 29th October 2006, while Rossi fell, the Kentucky Kid finished a safe third and became world champion. The emotion and elation on Hayden's face during the slow-down lap has become an unforgettable part of MotoGP history. Rossi, whose title duels normally descended into acrimony, was quick to offer congratulations to a rider he would always consider one of his best friends in the paddock.

In 2007 MotoGP changed from 990cc to 800cc engines, with Hayden given a miniscule RC212V that looked to have been designed around Pedrosa's proportions. In a season that saw Casey Stoner and Ducati dominate, Hayden never looked fully comfortable and was left to salvage three mid-season podiums for eighth overall.