Mark Loretta also extended his hitting streak to 12 games with a three-hit performance for Boston, which was also without Wily Mo Pena, who was a late scratch with recurring soreness in his left wrist.
"It was exciting," Loretta said. "I've never seen so many flashbulbs in a game in a ninth inning. It was almost hard to see the ball off the bat. The crowd was into it. I'm really happy for Curt. It was a big milestone for him."
Schilling (8-2) became the eighth active pitcher and 104th ever to reach the plateau. The 39-year-old left after seventh inning to a standing ovation and tipped his cap to the crowd as he made his way down the dugout steps.
Once the game was over, the sold-out Fenway Park crowd kept chanting Schilling's name until he emerged from the clubhouse to receive another standing ovation.
"I just know that walking out on that field after the game is an experience I'll never forget," Schilling said. "I'll never forget what those fans just did for me. Those are the things that when you're done playing, I think, they last forever, the memories that these fans can create for you."
The right-hander became the American League's first eight-game winner by scattering eight hits and allowing four runs over seven innings.
Nixon batted cleanup in place of Ramirez, who was on the bench to rest his back. With the game tied at 2 in the second, Nixon connected to left-center off Tampa Bay starter Seth McClung (2-6), scoring Youkilis and Loretta with the go-ahead runs.
"We scored some runs in that inning with two outs, that's always key, and then Curt was able to shut them down," Loretta said. "That's really our goal and objective at the top of the lineup -- to get on for the guys who normally drive in runs behind us."
"It was good to be out there for it," Youkilis said of being a part of Schilling's special night. "I just wish we could have scored more runs for him in support. Tampa Bay is fearless at times."
The Red Sox got to the Devil Rays right-hander for seven hits and six runs over five innings.
Youkilis also achieved a personal milestone in the game, starting in left field for the first time in his career and handling every chance cleanly. It was the fourth position for the first baseman, who had a chance to throw out Greg Norton in the second inning on a single by Josh Paul, but his throw was just up the first-base line.
"Manny just told me I was playing too deep in the beginning [of the game]," said Youkilis, who used a spare outfielder's glove belonging to Doug Mirabelli. "He said to play more shallow. Other than that, [he said] just catch the ball and throw the ball."
Keith Foulke pitched a perfect eighth and Jonathan Papelbon converted his 18th straight save to start the season, extending his Major League rookie record.
The Red Sox have won the first three games of the four-game set with Tampa Bay and maintain their two-game lead over the Yankees in the AL East.