The improbable triumph averted a Red Sox sweep, and it gave the Angels their first win at Fenway in five games this season.
"That's about as much of a roller coaster as you can be on," Angels manager Mike Scioscia said. "That's one of the best comebacks we've had. You don't put too much weight on any one win, but this one was certainly very special."
It was significant on two fronts -- the comeback by Santana, who once again resembled the 16-game winner from 2006, and the comeback in the ninth inning against a man once known as the most dominant closer of them all.
"Ervin throwing the ball the way we saw is going to be very big for us, and he's going to start next week for us [at Angel Stadium]," Scioscia said.
Working quickly and finding an excellent rhythm with Ryan Budde, who caught him all the way back at Class A ball, Santana retired 16 of the first 17 hitters he faced, throwing in the mid-90s consistently with a quality slider and changeup that kept hitters off balance.
Bidding for his 16th win, Josh Beckett was also on his game, yielding two runs (one earned) in seven innings. Santana gave up four hits and walked none while striking out five in 6 1/3 innings.
Yet the win slipped away from Santana as the Sox seized the lead on doubles by David Ortiz and Manny Ramirez in the eighth inning. Bullpen stalwarts Scot Shields and Francisco Rodriguez coughed up a rare late lead.
Undaunted, the Angels responded with their own display of resilience -- and it all started with Reggie Willits' 13-pitch marathon at-bat against Gagne to lead off the ninth. That ended with an out, but a toll was apparently taken on the big reliever.
After Gagne walked Kotchman on five pitches -- Erick Aybar was called in to pinch-run for Kotchman -- he surrendered a single to Figgins in another long duel. That put runners on the corners, and then Cabrera put one through the left-side hole to tie it at 5.
Up walked Guerrero, a man who doesn't like to waste time, and he promptly crunched the biggest of the blows to the left-center gap for his second and third RBIs of the night, giving him 96 for the season.
"We got some unbelievably clutch hits," Scioscia said.
The win went to Rodriguez (5-2) and the loss to Gagne (3-1).
Santana's 100th and final pitch was a double by J.D. Drew, putting runners on second and third for Justin Speier. After Ortiz scored on Mike Lowell's RBI groundout, Speier struck out Jason Varitek with a splitter to preserve a one-run lead in the seventh.
That advantage grew to three runs in the eighth, with Beckett having departed for reliever Manny Delcarmen. Guerrero tripled and scored on Garret Anderson's sacrifice fly before Gary Matthews Jr. hammered his 16th homer.
That's when everything caved in, starting with a pair of one-out walks issued by Shields and a single by Dustin Pedroia, loading the bases.
That brought Rodriguez into the fray, needing five outs for the save -- and he promptly bounced a pitch to Ortiz, allowing a run to score and the other two runners to move up. Then those two runners came flying home, tying the game, when Ortiz smacked a double to the left-center gap.
The crowd was still roaring when Ramirez laced a double into the left-field corner, delivering Ortiz with the go-ahead run.
One more comeback was on the way, and the Fenway partisans weren't as thrilled about this one.
Santana was a revelation, looking nothing like the man who struggled so severely this season that he was dispatched to Triple-A with a 5-11 record and 6.22 ERA.
Lifted by Santana's effort, the Angels seized the lead in the third. Cabrera singled to center with two outs and raced home when Guerrero's amazing strength enabled him to break his bat and still drive a ball into the left-field corner, where it kicked away from Ramirez momentarily as Cabrera was waved home by third-base coach Dino Ebel.
Julio Lugo's error on Guerrero's ground ball leading off the sixth led to an unearned run. Guerrero moved to third on Anderson's single, and he later scored when Maicer Izturis punched a single to right-center.
From the start, Santana exuded a calm confidence, taking his sign, rocking into his motion, delivering and keeping a nice tempo.
"I didn't want to give them a lot of time to think," Santana said through Angels coach Alfredo Griffin.
Budde, who collected his first Major League hit at Beckett's expense in the fifth, was moved to have a role in Santana's reemergence.
"That's the Ervin I've known since the beginning," Budde said. "He was confident, he had great stuff and he was putting it in good locations.
"The sky's the limit with Ervin. Maybe it took that [trip to Salt Lake] for him to say to himself, 'This is where I should be.'"