Simon (5-2) had a season-high eight strikeouts, walked one and hit one batter. Manny Parra got one out in the eighth and Aroldis Chapman struck out pinch-hitter Cesar Hernandez on a 102 mph fastball with runners on second and third for his second save in two tries.
Simon mixed a strong fastball with a slider and assorted off-speed pitches to keep the Phillies off-balance.
"I was trying to have fun out there," Simon said.
A couple of pitches were clocked in the low 70s.
"I don't know what he was throwing half the time," Mesoraco said. "I was just catching it and throwing it back."
The Phillies haven't scored a run in the last 20 innings and were shut out for the fifth time this season. They have lost four straight and eight of 10 to fall a season-worst five games under .500 at 17-22.
Kyle Kendrick (0-4) lost his ninth straight decision, dating to last Aug. 11. He allowed three runs and four hits in seven innings.
Kendrick hasn't had much help from the offense, however. The Phillies have been shut out five times in those 15 starts and have scored one run or less eight times.
"Main thing is I want the team to win," Kendrick said. "Just have to go out there, take care of my job and give my team a chance to win."
The Reds didn't have slugger Joey Votto because of a left distal quadriceps strain. The 2010 NL MVP remained in Cincinnati.
With Jay Bruce on the disabled list, it was the first time the Reds didn't have Votto and Bruce in their lineup since Sept. 20, 2012, at the Cubs.
Mesoraco provided all the support they would need. He ripped a three-run shot in his first at-bat since returning from his second trip to the disabled list.
"It was terrific. His first at-bat and he gave us an early cushion," Reds manager Bryan Price said.
Mesoraco was sidelined by a left hamstring injury. He arrived to the ballpark less than three hours before the first pitch after making the trip from Norfolk where he played three games for Triple-A Louisville.
"I was supposed to leave early this morning and didn't leave until about 3," he said. "I was starting to panic. I didn't feel that good. My legs were tired. Things cleared up after the first swing."
A reshuffled lineup didn't solve Philadelphia's hitting woes. Leadoff hitter Ben Revere was out with a stomach virus, so Jimmy Rollins batted first for the first time in 70 games. Carlos Ruiz moved up to bat second and John Mayberry Jr. took Revere's spot in center field.
The Phillies squandered a few chances in the early innings. They had runners on first and third with two outs in the first, but Simon struck out Marlon Byrd to end the inning. They had runners on the corners again with one out in the third, but Simon fanned Chase Utley and Ryan Howard. Simon struck out Ruiz to leave another runner on third in the fifth.
Votto had been the only Red to appear in the first 39 games. ... Reds cleanup hitter Todd Frazier was 0 for 4, ending his career-best 14-game hitting streak. .. Phillies manager Ryne Sandberg has used 22 different lineups in 39 games. ... Matt Beech was the last Phillies pitcher to have a losing streak of at least nine games. He lost 11 in a row between Aug. 13, 1996 and Aug. 2, 1997. ... Cole Hamels (0-2, 5.32) of the Phillies tries again for his 100th career win Saturday night vs. Homer Bailey (3-2, 4.72).
Copyright by STATS LLC and The Associated Press
PHILADELPHIA, PA - MAY 16: The tarp covers the field prior to the game between the Cincinnati Reds and...