Santana, who missed all of last season while recovering from shoulder surgery, lowered his ERA to 2.89 with the effort. The two-time Cy Young Award winner has broken the 100-pitch barrier just three times this season, but two have come in the last three starts.
The left-hander seemed poised to add his second win of the season on Wednesday, and manager Terry Collins opted to push him as deep as possible into the game. Santana -- who had already thrown 95 pitches -- was allowed to hit with a runner on third and a two-run lead in the sixth inning.
Rookie Todd Frazier pounded a solo homer off Santana in the seventh to draw the Reds within a run at 3-2, and the southpaw left after 107 pitches, one shy of his season high. The Mets escaped the seventh with the lead, but the Reds tied the game in the eighth and pushed ahead on another homer -- this one a two-run shot -- by Frazier.
"He's a good pitcher. It's tough," said Frazier of facing Santana. "He was an overpowering pitcher earlier in his career, and now he's changed everything. He's working a lot of different pitches. It's tough to pinpoint one, but you have to look for that fastball, get it and do something with it."
Cincinnati (19-17) opened the scoring in the third, but the Mets answered immediately in the bottom half of the inning. New York (20-17) forged a lead in the sixth on a run-scoring double by Ike Davis -- snapping an 0-for-16 skid at Citi Field -- and on a perfectly-executed suicide squeeze by Mike Nickeas.
The Mets elected not to hit for Santana with two outs in that inning, and the left-hander got two outs in the seventh before yielding to the bullpen. Jon Rauch, who relieved Bobby Parnell to start the eighth inning, recorded just one out and was charged with three runs en route to the loss.
Despite the loss -- and the Santana trend -- the Mets fell for just the second time in 18 games when leading after seven innings.
"Once I do my job and I'm out of the game, I just hope the guys can finish it," said Santana. "But again, it's out of my control and there's not much I can do. I just watch and hope that we get it done. That wasn't the case tonight. We've just got to wait for the next one and see if the results are different."
The Mets' bullpen has a league-high nine blown saves, and the relievers have combined for a 1-3 record and 8.69 ERA in the last seven games. The Mets elected to designate veteran D.J. Carrasco for assignment after the game, and Robert Carson will be recalled for Thursday's game.
"We've got to add on," said manager Terry Collins. "We're sitting there with two runs, three runs [or] four runs. If we can add on some runs, I think it would take a little heat off the bullpen too."
Rauch has now blown three saves, and he's notched a 12.71 ERA in his last seven outings. The towering right-hander gave up hits to Joey Votto, Drew Stubbs and Brandon Phillips in succession in the eighth inning, and Frazier wound up hitting his back-breaking home run off Carrasco.
"I've won two of his games, so it's really tough. I can't look the guy in the eye right now," said Rauch of Santana, his hard-luck teammate. "My inning cost the team a win. So yeah, I'm thinking about it."
The Mets hope that Davis can use his run-scoring hit as a springboard. New York's first baseman came into the game with the worst home batting average (.054) among all big league players, and he had only one hit at Citi Field since April 23. Now, with a double under his belt, Davis could use a spark.
"I thought his swings have been continually getting better," said Collins. "Of course, the big hit tonight, and hopefully he can get on a roll. I don't know what else to say, except that I hope he starts parlaying some of these hard hits into some balls that fall in for him so we can get his confidence back."