The South Carolina politician said in a statement he was stepping down to become president of the Heritage Foundation. His office said he would take the new job effective Jan. 1.
The 61-year-old Republican was first elected to the Senate in 2004. He previously served in the U.S. House for three terms.
"I'm leaving the Senate now, but I'm not leaving the fight. I've decided to join The Heritage Foundation at a time when the conservative movement needs strong leadership in the battle of ideas," DeMint's statement said. His office said DeMint was too busy to come to the phone.
Republican Gov. Nikki Haley gets to appoint his successor to the Senate. She gave no immediate indication who she might choose, or whether she would appoint herself. Haley spokesman Rob Godfrey says the attention should be on DeMint.
"Our state's loss is the Heritage Foundation's gain," Haley said in a statement.
DeMint's former state director, Luke Byars, said the senator's new role would allow him to effect change outside the U.S. Capitol.
DeMint, who previously ran a marketing firm, thought Republicans didn't do a good job communicating their message in the presidential race, he said.
"He knows how to communicate," said Byars, a political consultant. "This is a vehicle for him to push and pull on conservative issues on a national stage to get the attention of folks inside Washington. This lets him go back into something he loves. He's always been an idea guy."