"But we have a very different situation today. After nearly two years, 100,000 people killed, a rebel force comprised of al Qaeda and a Syrian regime in a much stronger position, a military strike would no longer be in our national security interest," the former Pennsylvania lawmaker said.
Santorum is considered a potential candidate for the Republican presidential nomination in 2016.
Before leaving the State Department, Clinton defended her role in the situation.
"I've done what was possible to do," she told reporters.