"Sometimes this season it seems like no matter what we do, it just isn't enough," Manuel said before a 4-3 loss to the Minnesota Twins in 10 innings Thursday night.
"This was definitely our shot to get in good position and we lost," Manuel said afterward. "This is tough to take."
Travis Fryman's dramatic ninth-inning home run gave Cleveland a hopeful reprieve, but the Indians stumbled again in the AL wild-card race.
"We're not dejected, but kind of somber," Fryman said. "We have to be thankful Oakland and Seattle both lost and we didn't lose ground."
Cleveland, which wasted a 2-0 lead and split the four-game series with the last-place Twins, remained 1 1/2 games back in the wild-card race, failing to take advantage of Oakland's 6-3, 14-inning loss to Anaheim.
The Indians close the regular season at home with a three-game series against Toronto starting Friday.
Oakland, a half-game behind AL West-leading Seattle, has three games at home against Texas, then a makeup game Monday night at Tampa Bay if necessary.
"This was a real tease," Indians shortstop Omar Vizquel said. "We played one of the most exciting games of the year with the chance to gain. Then we lose when they never hit the ball out of the infield."
Sandy Alomar, who flied out to the warning track in center with one out in the ninth as a pinch-hitter, was more upset.
"I feel like somebody died, my stomach hurts so much," he said. "I was so pumped up. I hit the ball 400 feet and made an out. Then they win like that."
Corey Koskie drove in the go-ahead run with a broken-bat, bases-loaded, fielder's-choice grounder off Bob Wickman (1-3).
"It was a special feeling for us," Twins manager Tom Kelly said. "What a ballgame. Very exciting."
Minnesota, which won the season series 8-5, loaded the bases on two infield hits and an intentional walk. Koskie then grounded a ball past Wickman that second baseman Roberto Alomar stopped with a dive behind the bag. He threw to Vizquel for a forceout as Luis Rivas scored from third.
Wickman was hit in the right hand by part of the bat on the play and was replaced by Steve Karsay, who got the third out.
"It's OK, we've got three games left and I'm ready to pitch," Wickman said. "The loss hurts a lot more than the hand."
Eddie Guardado (7-3) got three outs in the ninth and LaTroy Hawkins pitched the 10th for his 14th save in 14 chances. Kenny Lofton singled with one out, pinch-hitter Russell Branyan lined out to left, and Roberto Alomar singled Lofton to third against Hawkins.
With the sellout crowd chanting "Man-ny! Man-ny!" Manny Ramirez hit a sharp grounder to second that forced Alomar for the final out.
"They had their best batter up there," Hawkins said. "I just tried to throw strikes."
Fryman had hit the first pitch from reliever Bob Wells in the bottom of the ninth for his 22nd homer, tying the score at 3. The ball hit just above the yellow line atop the left-field wall and originally was ruled a double. With Manuel and several Indians players protesting, the umpires got together to discuss the call and signaled home run.
"That gave us life," Manuel said. "We put everything we had into this game, but just got beat."
The homer deprived Twins starter Eric Milton of his 14th win. He allowed two runs and six hits in eight innings, struck out nine and walked two.
"There's nothing like going out and pitching in front of 40,000 fans when they are all hyped up," Milton said.
Cleveland's Bartolo Colon, who is 6-0 since July 26, left with the Indians behind 3-2.