Aided by an umpire's missed call and an incredible catch by a left fielder who grew up in Queens as a Mets fan, Santana's start is also the first no-hitter of his career.
In the 8-0 win over the St. Louis Cardinals, Santana, who missed last season because of shoulder surgery, walked five and struck out eight, while testing the limits of his comeback.
Mets manager Terry Collins said before the game that he wanted to limit Santana to a maximum of 110-115 pitches. Santana finished with a career-high 134.
Afterward, an emotional Collins expressed his trepidation about going after history instead of preserving Santana's long-term health.
"I just couldn't take him out," Collins said.
In the ninth inning with 27,609 fans all standing, Santana's final pitch, a 3-2 change-up, resulted in David Freese swinging and missing. Santana's teammates all stormed the mound to celebrate.
Santana said he never has thrown a no-hitter at any level.
"I don't think I've ever even thrown a no-hitter in video games," Santana said.
The San Diego Padres, established in 1969, are now the only team in the majors without a no-hitter. The Mets previously had 35 one-hitters.
During his postgame news conference, an emotional Collins lamented his decision to keep Santana in the game because of fear of damaging the shoulder.
"I'm very excited for him, but in five days, if his arm is bothering him, I'm not going to feel very good," Collins said.
In the dugout, during the Mets' three-run seventh inning, Collins told Santana he was his "hero" and then he handed the decision of if he wanted to stay in or not to Santana.
"I just said, 'Look, I tell you guys every day you have a say in what goes on here,' " Collins said. " 'You have a voice and your voice is going to be heard.' "
Santana was never going to remove himself. In reality, the no-hitter probably should have been over before the seventh.
To start the sixth, Carlos Beltran, in his first game at Citi Field since leaving the Mets last year, scorched a shot down the line. A replay showed Beltran hit the white chalk on the third-base line. Umpire Adrian Johnson ruled it a foul ball and Beltran ended up grounding out.
"I saw the ball hitting outside the line, just foul," Johnson said to a pool reporter after the game.
Johnson said he saw the replay, but upon further review, declined to comment if he thought the ball was fair or foul.
In the seventh with one down, left fielder Mike Baxter -- who grew up in Whitestone, Queens, 10 minutes away from old Shea Stadium and Citi Field -- made a catch to save the no-hitter, going back on a bullet from Yadier Molina.
Baxter, running to the wall, extended his glove and made a catch. As he stepped on the warning track, Baxter did not slow down.
His body, leading with his shoulder and his head, violently slammed into the wall and he collapsed to the ground.
"That ball that Baxter caught, he'll go down in the annals of New York Met lore because of that," said pitcher R.A. Dickey.
Collins and team trainers ran out to left field. Baxter eventually got to his feet and walked off the field. The crowd gave him a standing ovation.
The Mets announced Baxter has a left-shoulder bruise but was undergoing further testing.
"What a night for the Mets," Baxter said in the Mets' clubhouse. "As a Met fan as a kid, it is a huge night for the Mets. We have been waiting a long time for a no-hitter."
Friday night added to an incredible comeback from shoulder surgery for Santana, who is now pitching as well as when he was perennially a Cy Young Award contender.
With two outs in the eighth, the fans chanted "Johan! Johan! Johan!" Santana walked Rafael Furcal on his 118th pitch, and Collins came out to talk with Santana.
Four pitches later, Santana got Beltran to hit a meek infield liner that second baseman Daniel Murphy snared.
During the bottom of the eighth, Santana sat away from his teammates at the end of the dugout, awaiting his chance at history. He then made it happen for a franchise that has been trying since 1962.
After the final out, Santana did interviews with the Mets' TV and radio station before he walked into the clubhouse. Dickey said it was like they were waiting for the king. Dickey and his teammates had champagne waiting for Santana.
"We did this together," Santana said. "It is not just about me. We had a great, great game tonight. Everyone participated. We did the little things the way we were supposed to do it. And it worked out good. I thanked them because we as a team made history tonight."