Simon can become the NL's first 11-game winner Saturday night as the visiting Reds try for a fourth straight victory while looking to hand Cain his fourth consecutive losing start.
After going 3-9 with a 5.15 ERA in 19 starts over six seasons prior to 2014, Simon (10-3, 2.92 ERA) has thrived as part of a Cincinnati rotation led by major league ERA leader and Friday's winner Johnny Cueto.
Since giving up five runs and walking four in 3 2-3 innings of a 6-3 loss at Dodger Stadium on May 27, the right-hander is 4-0 with a 2.94 ERA in five starts this month.
Simon yielded a homer in seven innings but did not factor in the decision of a 6-1 victory at Wrigley Field on Monday. He's 7-1 with a 2.50 ERA in nine road starts.
"Not that I don't think he has had the ability to do it, it's just this guy - really from a guy that had 19 major league starts before this season - to do what he's done this year is spectacular," Reds manager Bryan Price said.
Though Simon is making his first start against the Giants (46-34), he's posted a 4.50 ERA without factoring in the decision over three relief appearances versus San Francisco.
Cueto allowed two runs and three hits in 8 1-3 innings and Todd Frazier had three hits as Cincinnati (41-38) won for the 12th time in 16 games, 6-2 on Friday. Including the playoffs, the Reds have won three in a row and nine of 11 at AT&T Park.
San Francisco has dropped two straight and 13 of 17, trimming its NL West lead over the Los Angeles Dodgers to two games.
Cain (1-6, 4.82), who recorded his only win May 15, has allowed 18 runs and 20 hits in 17 1-3 innings while dropping three consecutive starts. The right-hander gave up six runs in 7 1-3 innings of a 6-0 home loss to San Diego on Monday.
"He's human. I'm sure he's frustrated," Giants manager Bruce Bochy said. "I can tell you he's probably getting a little tired of it. He gives you all he has every game he pitches, and he did tonight. We couldn't get any runs for him. It was a better outing but I'm sure it's wearing on him."
Cain last faced the Reds in 2012, when he went 1-3 with a 5.32 ERA, including two starts in the NLDS.
He's never faced Frazier, who is batting .468 with 13 RBIs during a 13-game hitting streak against the Giants that includes the postseason.
Teammate Jay Bruce is hitting .452 with nine RBIs in his last eight contests overall, and .477 with 11 RBIs during an 11-game regular-season and playoff hitting streak at San Francisco.
"I have an approach I think works and I keep chipping away," Bruce said.
Hunter Pence and Pablo Sandoval had two of the Giants' three hits Friday. That duo is a combined 0 for 4 versus Simon.