Lee will be part of a delegation headed to Bangalore, India, to meet with government and business leaders as part of the San Francisco-Bangalore Sister City Initiative.
The mayor recently returned from a trip to China, where he said he agreed to two new sister-city partnerships.
Lee spoke to reporters in San Francisco earlier this week and shot down rumors that his overseas trips might presage a move to be the new U.S. ambassador to China after current ambassador Gary Locke announced earlier this month that he was stepping down from the post.
"I'm not interested in being the ambassador to China," Lee said.
"I'm 100 percent on the job as the mayor of San Francisco," he said.
Lee, who also traveled overseas to Ireland and France earlier this year, said that the obligations of being the mayor of an international city like San Francisco "is going to fulfill any interest I have in being part of any international conversation."
The mayor's trip to India is scheduled through Dec. 5.