Hamels became the seventh pitcher and fourth lefthander since 1900 to win 100 or more games as a Phillie.
"Cole was outstanding for his 100th career win," manager Ryne Sandberg said. "It is by far the best he has looked this year with his velocity, command, throwing strikes, and using all his pitches."
Hamels' previous win came Sept. 14, when he beat the Washington Nationals, 5-4. He went the final two games last year and first four this season without a victory.
For the second straight game, Hamels allowed just one run and struck out 10 in seven innings. That gave Hamels 25 career double-digit strikeout games, tying him for third on the Phillies list with Jim Bunning. (Steve Carlton is No. 1 with 70.)
One difference between the last two games was the pitch count: He threw a career-high 133 pitches in his last game, and this time Hamels limited the total to 90.
The offense was led by two players who moved to different spots in the batting order. Domonic Brown moved from sixth to seventh and contributed a home run, double, and career-high five RBIs. Cody Asche hit sixth for the first time this season and went 2 for 4 with three RBIs.
Asche's two-run double broke the Phillies' scoring drought in the fourth.
"I have been more comfortable, taking balls and swinging at strikes more," Asche said.
Brown followed Asche with a towering two-run home run in the second deck in right field on a 3-0 fastball for his second home run of the season. Counting last year, Brown had hit one home run in his previous 257 plate appearances before his two-run shot.
A Carlos Ruiz RBI single ended the evening for Reds starter Homer Bailey, and Chase Utley completed the fourth-inning scoring with an RBI single.
The Phillies' six runs in the fourth tied their season high. That came on opening day, when they scored six in the second inning of a 14-10 win at Texas.
For the second straight game, Jimmy Rollins batted leadoff and Ruiz hit second. Ben Revere missed his second straight game with a stomach virus, but upon the leadoff hitter's return, manager Ryne Sandberg could be tempted to keep Rollins and Ruiz at the top of the order.
But this was Hamels' night, for sure.
"A lot of these teammates were here for the very first win all the way to 100," Hamels said. "[It is] especially [special] for a great organization and great fans. They have seen quite a few wins here personally or on Comcast, and it is nice to be able to do it for everybody."