Lyles looks to continue his emergence as the Rockies' top starter Saturday night and help them avoid a three-game skid against Simon and the Reds.
This game could also feature the return of Cincinnati closer Aroldis Chapman, who was activated from the disabled list Saturday. He underwent surgery to repair damage after being struck in the left eye and nose by a line drive during a spring training game March 19.
The flame-throwing Cuban was hit hard in a pair of minor league rehab appearances this week, but reportedly had good velocity and felt fine.
As Chapman had 38 saves each of the last two years while developing into one of baseball's top relievers, Lyles (4-0, 2.62 ERA) was largely disappointing through his first three seasons in the majors.
Lyles was 22-50 with a 5.35 ERA for Houston, but he's been outstanding since Colorado acquired him in a four-player trade in December. The 23-year-old right-hander owns the rotation's lowest ERA and WHIP (1.05) while leading the team with 44 2-3 innings.
"An opportunity to get an arm like this at this age, who was a horse - there were a lot of reasons to like this kid," manager Walt Weiss told the team's official website.
The Rockies (22-16) could use another strong outing from him after getting six hits and surrendering a walkoff solo homer in a 4-3 loss to Cincinnati (16-18) in Friday's series opener. That came a day after they were held to five hits in a 5-0 loss at Texas.
Lyles may not need much support from the offense after allowing two runs in eight-plus innings of an 8-2 win over the Rangers on Monday.
"The biggest thing is making better pitches when guys are in scoring position. I don't know the numbers but I can figure I wasn't too good in the past," Lyles said.
Opposing hitters are 5 for 24 (.208) with runners in scoring position against Lyles, who kept the Rangers hitless in three at-bats in that scenario. He surrendered a .321 average and 11 homers while with the Astros.
He'll now face the Reds for the first time this year, and he's 2-1 with a 5.79 ERA in five games against them, including four starts. He was pummeled for nine runs in 3 1-3 innings of a 10-0 loss against them Sept. 17.
Lyles' success has been just as unexpected as that of Simon (4-1, 1.99), who spent his first two years with the Reds as a reliever.
The right-hander went 3-9 with a 5.15 ERA in 19 starts with Baltimore from 2008-11 before Cincinnati inserted him into the rotation this year. So far, he's been superb with the team's second-best ERA among its starters behind Johnny Cueto's MLB-best 1.43.
Simon has also completed at least six innings in each of his six outings and is 3-0 over his past four. He tossed just 80 pitches while going seven innings Sunday, allowing three runs and two homers in a 4-3 win in 10 against Milwaukee.
Simon is now scheduled to get his first start against the Rockies, and he has no record while allowing three runs in 7 2-3 innings over five relief outings against them.
He'll also try to keep Nolan Arenado without a hit for a second straight game after he was 0 for 3 with a walk and a strikeout Friday, ending his team-record 28-game hitting streak - the longest in the majors this year.
The third baseman, who is 1 for 9 over his last three meetings with the Reds, had a .360 average with 11 doubles and 20 RBIs during the streak.
Joey Votto may be hoping he's snapped out of his recent funk after connecting for Friday's game-winning shot, ending an 18-game homer drought. It was also the first baseman's only RBI during an eight-game stretch in which he's gone 7 for 33 (.212).
Votto, though, is 6 for 9 with two doubles and a homer off Lyles.