More than 215,000 people have been killed and half of the country's population displaced, prompting human rights groups to accuse the international community of "failing Syria."
Amid the dragging stalemate on the ground, the country has been carved up between government forces, jihadist groups, Kurdish fighters and the remaining non-jihadist rebels.
Diplomacy remains stalled, with two rounds of peace talks achieving no progress and even a proposal for a local ceasefire in the second city Aleppo fizzling out.
"Well, we have to negotiate in the end. We've always been willing to negotiate in the context of the Geneva I process," Kerry said in an interview with CBS television aired Sunday.
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Deputy State Department spokeswoman Marie Harf, however, denied there was any shift in US policy.
"@JohnKerry repeated long-standing policy that we need negotiated process w/regime at table - did not say we wld negotiate directly w/Assad," she said in a message on her Twitter account.
"That's underway right now. And I am convinced that, with the efforts of our allies and others, there will be increased pressure on Assad."
The conflict began as an anti-government uprising, with protesters taking to the streets on March 15, 2011, inspired by similar revolts in Egypt and Tunisia.
But a fierce government crackdown on the demonstrations prompted a militarization of the uprising and its descent into today's brutal multi-front conflict.
The full toll is likely to be even higher, because the fate of tens of thousands of missing people remains unknown.
The UN refugee agency UNHCR says Syria is now "the biggest humanitarian emergency of our era.