It was the Senators' first loss in regulation at home this season (4-1-3).
James van Riemsdyk and Josh Leivo had second-period goals to help Toronto (8-5-2) overcome 2-1 and 3-2 deficits. Santorelli's shorthanded goal at 10:53 put the Maple Leafs ahead to stay, and David Clarkson scored an insurance goal 6:06 into the third period when he deflected a shot by defenseman Morgan Rielly between the pads of goaltender Robin Lehner.
"I thought it was a big goal for our team at that stage of the game," linemate Peter Holland said of Santorelli's winner.
Holland won a puck battle with Senators captain Erik Karlsson and found Santorelli coming down the slot.
"I knew [Santorelli] was kind of coming in behind me," he said. "Once I got the puck back from Karlsson, I was trying to look for him and he made a great shot to put it over the glove."
The Maple Leafs overcame three one-goal deficits before scoring the final three goals.
"We kind of started a little slow, but we found our way," Santorelli said. "We stuck with it when we were behind and we ended off a good weekend for us."
Toronto goaltender James Reimer made 38 saves and has a 10-2-1 career record against the Senators. Lehner finished with 25 saves for Ottawa (7-4-3).
Sunday started with both teams visiting the National War Memorial where Cpl. Nathan Cirillo was shot and killed during an attack on Parliament Hill on Oct. 22. The teams were scheduled to play at Canadian Tire Centre that night, but the game was postponed until Sunday.
"It's a little unusual to meet together in the morning and pay our respects, but it was a great thing to do and I think both clubs would do it again if need be," Reimer said. "This week and Nov. 11 mean so much. You really don't want to take for granted all that the people have gone before us have done. To pay our respects and thank them, I think, is huge."
The Senators continue to have trouble getting or maintaining momentum in the second half of games.
"I thought as the game went on, their competition level continued to rise, and ours lowered," Senators coach Paul MacLean said. "To me, that ended up being the difference in the game. Over the 60 minutes, they were more competitive than we were on a shift-by-shift basis."
The Senators got one point from two home games this weekend; they lost 2-1 to the Winnipeg Jets in a shootout on Saturday and were unable to hold off the Maple Leafs one night later.
"In the past couple of games we've been better, we've been building," said Senators center Kyle Turris, who scored Ottawa's second goal, his first in 13 games. "But today was a setback. It's something we'll work on, improve and move forward."
Van Riemsdyk tied the game 2-2 at 2:33 of the middle period when he swept around Senators forward Bobby Ryan, back in the lineup after missing the shootout loss to Winnipeg, at the Ottawa line and fired a shot that hit Lehner in the shoulder and popped up in the air. The puck landed near the left post; van Riemsdyk tracked it down and banged it in for his sixth goal of the season.
The Senators went ahead 3-2 on a goal by Mark Stone at 4:04. It was Ottawa's eighth power-play goal on home ice this season. They had 16 at Canadian Tire Centre all of last season.
But the Maple Leafs tied it for the third time at 6:21 when forward Trevor Smith, called up for the game from the Toronto Marlies of the American Hockey League with Daniel Winnik out with a head injury, helped win a board battle against Karlsson on the left wing. Smith centered the puck to Leivo, who beat Lehner for his first goal of the season.
The Maple Leafs have been getting some good work from their call-ups. Leivo was recalled on Saturday.
"One thing you can say about those kids, they are not a liability defensively," Toronto coach Randy Carlyle said. "You are going to have to earn what you get from them. They're hard players to play against in the defensive zone."
Mike Hoffman opened the scoring with his fourth of the season for the Senators and Holland tied it on a play that ended with a delayed reaction by the players on the ice. Holland's shot hit the stick of Ottawa defenseman Cody Ceci, then hit Lehner's stick, deflected up and lodged in the top of the net. Santorelli pointed at the puck from behind the net and the goal was confirmed by video review.
With the win, the Maple Leafs completed a sweep of back-to-back games. They defeated the New York Rangers 5-4 at home Saturday.
"Tonight's game was similar to last night's game," Carlyle said. "There were some goals that were scored that you think mistakes were made that were easily correctable. That's the game. We found a way to maybe make less mistakes than the opposition tonight. It's as simple as that."