Seven years, four All-Star appearances, 255 saves and one Tommy John surgery later, Nathan is the best closer the Twins have ever had.
"Just with the surgery and everything, the bumps in the road, I think it made it mean even more," said Nathan, who missed all of last season with the elbow surgery. "To be able to come back and accomplish this, more importantly we got a win and obviously we needed some wins."
Thome also had a run-scoring single and the Twins got an outstanding effort from Nick Blackburn to snap a six-game losing streak and avoid a sweep.
David Ortiz went 2-for-4 with a homer and Lester gave up four runs and eight hits in 7 1/3 innings for the Red Sox. The left-hander also issued five walks, tying a season high.
"I felt like I had pretty good stuff, but I just wasn't able to locate," Lester said. "I gave them too many opportunities. When you do that, that's what happens."
For a while it was unclear if Nathan would even get a chance to break the record.
The Red Sox were losing 2-1 when Ortiz stepped into the box in the eighth against lefty Glen Perkins, who has been dominant this season but has struggled a bit in the past week.
It was power against power, and Perkins gave him straight gas the entire showdown. He hit 96 mph on six pitches before cranking up and reaching 98 on his final offering to Ortiz, who sent the pitch 419 feet into the bullpen behind center field. It was the first homer off Perkins this season in 178 plate appearances.
Success against his former team is nothing new for Ortiz, who was allowed to leave the organization after the 2002 season. He is hitting .333 (54-for-162) with 12 homers against the Twins, and is 9-for-19 (.474) at Target Field.
But Thome ripped a double to the left-center field gap to score Joe Mauer, Danny Valencia added an RBI double and Tsuyoshi Nishioka came through with a run-scoring single off Alfredo Aceves to give Nathan a little breathing room heading into the ninth.
"To get No. 255, it's obviously an honor to me to pass such a great pitcher in Aggie," Nathan said. "A good human being. To be able to take over his record means a lot to me."
Nathan never would have had the chance if not for Blackburn's sharp performance.
"It was the kind of effort he needed and the kind of effort we needed," Twins manager Ron Gardenhire said.
Few could say they saw this outing coming from him. In his previous eight starts, he was 3-5 with an 8.15 ERA and 65 hits allowed in 38 2/3 innings. He had allowed 16 earned runs in his past three starts.
All he did was handcuff one of the deepest, most formidable lineups in the game for almost seven innings. With a biting sinker and a befuddling changeup, Blackburn held the highest-scoring offense in the majors scoreless through six as the Twins took a 2-0 lead.
Perkins (4-2) gave up one run and two hits in 1 1/3 innings for the win.
Aviles had two hits for the Red Sox, and Delmon Young went 2-for-2 with two walks for the Twins.
The 34-year-old Nathan did a little reflecting on Wednesday night. He played shortstop in college at little Stony Brook in New York and didn't start pitching until he reached the minor leagues in San Francisco's organization.
"He's been through an awful lot and there's been a lot of people in the baseball circles who said at his age he probably wouldn't be able to come back and be anywhere close to the closer he's been," Gardenhire said. "But I think through a lot of hard work and dedication on his part, and a few ups and downs, he's getting back to being that dominant closer again."
The Twins got some good news earlier in the day when Gardenhire announced Justin Morneau will be activated from the disabled list on Friday in Cleveland. Morneau has been out since June 9 after having neck surgery. ... Red Sox 2B Dustin Pedroia was given the day off. "He was fighting me on it the last two days," manager Terry Francona said. "Last night after the game, he's like, 'I'm tired.' This will be really good for him." ... Francona disputed a call in the sixth when umpire Ted Barrett gave the speedy Ben Revere home on a double by Mauer that was caught by a fan. ... Perkins has given up five runs -- four earned -- in his past three appearances. He had an 11-appearance scoreless streak before that. ... The Twins are off Thursday and will begin a three-game series against the Indians in Cleveland on Friday. Carl Pavano (6-9, 4.71) will take the mound for the Twins against Justin Masterson (9-7, 2.71). Thome will continue his pursuit of career homer No. 600 in the place where his career began. He is two away from becoming the eighth player to reach the mark. ... The Red Sox are off Thursday as well and will head to Seattle for a three-game set against the Mariners starting on Friday. John Lackey (10-8, 6.14 ERA) will start Game 1 for Boston against Blake Beavan (3-2, 2.83 ERA). Lackey has been improving lately after a dreadful start. He allowed three runs in six innings in his previous start against the New York Yankees.