Kerry was first heading to Seoul for talks on North Korea, after Pyongyang for the second time scrapped an invitation to a special US envoy to visit for discussions on the fate of jailed US tour operator Kenneth Bae.
The top US diplomat will arrive Thursday, a day after North and South Korean officials sat down for their highest level talks for years ahead of a planned reunion of family members divided by the Korean War.
Frictions with the North will top the agenda as Seoul and Washington also prepare for joint military drills which have been denounced by Pyongyang.
Washington has repeatedly called for the isolated North to release Bae, a devout Christian Korean American who was sentenced to 15 years' hard labor last year.
The State Department on Tuesday again voiced frustration that an invitation to US envoy Robert King was extended on February 5 but withdrawn just three days later.
"North Korea is attempting to link Kenneth Bae's case to unrelated military exercises. As you've heard us say many times, there is no connection," State Department spokeswoman Jen Psaki said, renewing fears for Bae's health.
The North wants to resume talks with Seoul and Washington on its nuclear program, but both have insisted Pyongyang must first make a tangible commitment to abandoning nuclear weapons.
From Seoul, Kerry will travel to Beijing, Pyongyang's main ally. Kerry is likely to highlight the need to tackle climate change by the world's top emitters of greenhouse gases.
But he will also seek to clarify with Chinese leaders an upswing in tensions after Beijing last year unilaterally extended its air defense zone over disputed islands in the East China Sea.
Last Friday, Kerry reaffirmed a 1960 treaty with Japan and vowed the US would defend its ally against attack, including over the islands claimed by China.
There are also concerns about Beijing's intentions in the South China Sea, which it claims almost in its entirety -- even areas far from its shoreline -- but portions are also disputed by Brunei, Malaysia, the Philippines, Taiwan and Vietnam.
Kerry's trip -- his fifth to North and Southeast Asia since taking office a year ago -- will also take him to Indonesia, before he heads to Abu Dhabi. He is due back in Washington on February 18.