Senior officials will meet in Beijing tomorrow and on Thursday for the sixth Strategic and Economic Dialogue, billed as the main annual meeting between the world's two largest economies.
Kerry departed from Andrews Air Force base, outside of the US capital, for the long trip.
Despite the Obama administration's famous "Asia pivot," already fraught relations have strained further since the Washington in May indicted five Chinese military officers for hacking into US businesses.
Alarm is also growing in Washington over Beijing's increasingly assertive moves to stake out its claims to swathes of the South China and East China Seas -- pitting it against regional neighbours, many of whom are strong US allies.
While the US takes no sides in the competing territorial claims, it has accused Beijing of destabilising acts and urged the Chinese to uphold freedom of navigation in the key waterways.
"The trick of course is to manage friction in an effective and constructive way," Assistant Secretary of State Daniel Russel told AFP.
China, on track to overtake the US in the coming years as the world's top global economy, has accused the United States of seeking to rein in its growing clout. Some Chinese officials have also sought to dismiss the US as a country in decline.
Kerry and Treasury Secretary Jacob Lew will lead a large US delegation to meet State Councillor Yang Jiechi and Vice Premier Wang Yang, who will head Beijing's team.
"There is a growing body of evidence that points to direct Chinese government involvement" in hacking, Russel said.
"Clearly to us that means that the Chinese government has the ability to stop it," he insisted.