Locke, 63, known for his affable, non-confrontational style, said he has informed President Barack Obama about his decision to quit by early next year.
Locke, who also served in the Obama administration as Secretary Commerce, faced two of the most sensitive diplomatic episodes between the two countries during his tenure here.
He, however, successfully handled both the crises over the entry of Chen Guangcheng, a persecuted human rights activist, into US embassy here and defection of a high-profile police chief to US Consulate in Chengdu.
Locke has made positive efforts to promote exchanges and cooperation between China and US, Chinese Foreign Ministry spokesperson Hong Lei said.
He lauded Locke's efforts for last successful meeting between Obama and Chinese President Xi Jinping in June which provided a clear direction for establishing model of major country relations between China and US.
"We hope we can make constant progress in this regard," Hong said.
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