CNN and NBC projected Romney the winner, with the Pennsylvania secretary of state's Web site showing him with 55.8 percent of the votes with 21.6 percent of the precincts reporting.
Though he pulled out of the race April 10, Santorum still was polling 19.6 percent in his home state, which he once represented in the U.S. Senate.
The victory in Pennsylvania, where 72 delegates were contested, was the fourth of the night for Romney. He also took Connecticut, Delaware and Rhode Island, with only New York yet to be counted.
Romney, the former Massachusetts governor, went into the day's primaries with an estimated 695 delegates, CNN said. He needs 1,144 to officially become the GOP's nominee.
Gingrich and Paul trail far behind in the delegate count.
Celebrity Couples of 2014 [PHOTOS]