Wolin, 51, has served more than four years in the administration of President Barack Obama.
He will step down at the end of August, the Treasury said in a statement.
The Treasury had previously announced Wolin would stay through a period of transition after Treasury Secretary Jacob Lew took office in late February.
Wolin had been acting Treasury secretary after Lew's predecessor, Timothy Geithner, departed in mid-January.
He was confirmed as deputy secretary in May 2009 and is the longest-serving deputy secretary in the department's history.
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"For more than four years, Neal has played a key role on my economic team," Obama said in the Treasury statement.
"His deep knowledge and excellent judgment helped us prevent a second Great Depression, pass tough new Wall Street reform, strengthen our financial system, foster growth here at home, and promote economic development around the world."
Wolin is planning to take a post with a think tank "as he mulls other options outside government," The Washington Post said.