Hamels, aided by a triple-play in the fifth inning, pitched his first career complete game and struck out a career-high 15 batters to lift the Phillies to a 4-1 victory over the Reds before a sellout crowd of 39,353 at Great American Ball Park.
Jeff Conine hit his second home run of the season in the second inning, but it wasn't enough to back starter Eric Milton, who had perhaps his best outing of the season.
Milton (0-3) allowed three runs, two earned, on six hits in six innings. He had no walks, one strikeout and recorded eight ground-ball outs en route to his first quality start since Aug. 24, 2006.
"It's been tough this year," Milton said. "I've been putting a lot of work in, especially on my sinker. I guess I can take some positives from today. But, their guy was better. Two runs in the first inning were all he needed."
A defensive miscue led to those two Phillies runs.
With Shane Victorino on first base and one out, Edwin Encarnacion fielded Jimmy Rollins' ground ball and threw wide to second base, pulling Brandon Phillips off the bag to prevent a potential inning-ending double play.
Chase Utley followed with a two-run double to give the Phillies a 2-0 lead.
Following Utley's double, Milton retired nine of the next 10 batters he faced.
"We had a chance for a double-play ground ball to get out of that [first] inning," said Reds manager Jerry Narron. "I thought Miltie pitched well for us. He got more ground balls than normal. Hopefully he can continue to throw strikes and keep the ball down."
Hamels (2-0) struck out the side in the first inning.
But, Conine greeted him with a home run on the first pitch of the second inning to make the score 2-1.
Still trailing 2-1 in the fifth, the Reds had Josh Hamilton on second and Encarnacion on first with nobody out.
Just when it appeared the Reds were about to break through against Hamels, the Phillies turned in a rare defensive gem to squelch the rally.
Phillies third baseman Abraham Nunez fielded a sharply hit ground ball by Ross, stepped on third and threw to Utley to force Encarnacion at second. Utley's relay to first baseman Wes Helms beat Ross by a step to complete a 5-4-3 triple play.
"I ran as hard as I could," said Ross.
It was the first triple play turned in the Major Leagues this season, and the first by the Phillies since May 15, 1999.
The last one turned against the Reds was on May 19, 1997, when catcher Eddie Taubensee lined into a triple play against San Diego.
"I've seen a couple of triple plays, but not a 5-4-3 like that," Narron said. "All I can tell you is that it was a tailor-made triple play."
Aaron Rowand hit a solo homer off Victor Santos with two outs in the eighth to provide the winning margin for Philadelphia.
The Reds had runners on first and third with two outs in the eighth, but Hamels fanned Adam Dunn to end the inning.
The 15 strikeouts were the most by Reds batters in a nine-inning game since April 4, 2005, when they struck out 16 times against the New York Mets.
Hamels' previous career high was 12 strikeouts, accomplished twice.
"He pitched well against us last year," said Narron. "He's one of the better young pitchers in baseball."
Hamels faced the Reds in his Major League debut May 12, 2006, at Great American Ball Park, allowing just one hit in five innings. He held the Reds hitless for 4 2/3 innings in that start.
"He's got good stuff," said Ross. "He's got a changeup that falls off the table. He mixes up his pitches, which is what makes most good pitchers tough."
Encarnacion, who entered Saturday's game hitless in 10 at-bats, went 2-for-3.
The Reds are 2-6 against left-handed starters this season. Entering Saturday's game, they were hitting just .202 against left-handers.
"We really haven't had anyone get hot for us," said Narron. "We haven't had some guys swing the bats for us. That'll come around.