The 53-year-old Republican candidate made the announcement on "Good Morning America" Monday, vowing he's "in it to win."
In the network interview, Santorum accused President Barack Obama of having a weak foreign policy, saying he doesn't feel he has stood up sufficiently to Iran and asserting he has done too little to speak out against Syrian President Bashir Assad for the violence there.
He'll be counting on support from social conservatives to stand out from the rest of the Republican candidates.
Santorum has enjoyed strong support in the past from the anti-abortion rights bloc in the Republican Party, and he enters the race four days after former Massachusetts Gov. Mitt Romney formally declared his candidacy.
Santorum served several years in the House of Representatives before becoming the No. 3 Republican in the Senate. He lost his re-election bid in 2006, but Santorum says his record of sticking by his principles will resonate with voters.
The Associated Press contributed to this story