The right-hander looks to win his sixth straight decision while cooling off the surging Arizona Diamondbacks on Wednesday night.
San Francisco clinched its second division crown in three years with a win over San Diego on Saturday, but it has dropped two straight since after falling 7-2 to Arizona in Tuesday's series opener.
The Giants (89-65), who had won 10 of 11 prior to Sunday's loss to the Padres, mustered only four hits - their fewest since they also finished with four in a loss to the Diamondbacks on Sept. 5.
Arizona has won seven of nine, but Cain (15-5, 2.86 ERA) will look to cool it down while extending his unbeaten run to nine.
Cain has allowed more than two runs only once while posting a 2.45 ERA over his last eight starts. He gave up one run and struck out eight in eight innings of last Wednesday's 7-1 win over Colorado to set a career high for victories.
''It feels good to finally get past that 14 number,'' Cain said. ''But you know what? We've got games left, and I don't want to stop now.''
The right-hander won his last two starts versus the Diamondbacks while allowing only one run in each, striking out eight in six innings May 12 and overcoming five walks in five innings Sept. 14.
Cain is 4-1 with a 2.26 ERA over his last eight home starts versus Arizona (78-76), which still is officially in the playoff race but sits 5 1/2 games behind St. Louis for the NL's second wild card.
Paul Goldschmidt, who extended his hitting streak to eight, finished with a career-high five RBIs after hitting a three-run homer and adding pair of sacrifice flies Tuesday. Aaron Hill scored three times while going 3 for 5.
''The pitch I hit tonight was up a little bit and the wind brought it back a little. It barely cleared the fence," Goldschmidt said. "I wish I knew how to explain it. I'd try to do it more often. Every time I step in I just want to hit the ball hard and swing at the right pitches.''
The Diamondbacks have won four of five in San Francisco, and they'll send Wade Miley to the hill as he looks to get back on track Wednesday.
Miley (16-10, 3.25) has gone through a rough patch over the last month, going 2-2 with a 5.34 ERA in his last five starts. He gave up five runs and a career high-tying 10 hits Friday against Colorado, but the offense picked him up in a 15-5 victory.
The left-hander didn't get nearly the same support Sept. 15 against the Giants, allowing three runs in seven innings of a 3-2 defeat. He earned a win in relief versus San Francisco on April 8, pitching four hitless innings.