In a rematch of an earlier showdown, Simon takes the hill opposite Samardzija on Tuesday night after Monday's series opener was postponed due to rain.
Simon (3-1, 1.30 ERA) has given Cincinnati a huge lift, surrendering two runs or fewer in each of his first four outings while holding opponents to a .172 average. The right-hander is looking to win a third consecutive start after allowing two runs and four hits over 6 2-3 innings in Wednesday's 5-2 victory at Pittsburgh.
"He's been terrific," manager Bryan Price said. "He's been an extremely versatile pitcher for us the last two-plus seasons. He's always been a talented guy, but he's really found himself and made himself into a very good-looking starting pitcher."
Simon also shined in a 4-1 win at Wrigley Field on April 18, allowing one unearned run over six-plus innings opposite Samardzija.
"We just weren't able to do a whole lot offensively," Cubs manager Rick Renteria said afterward.
Samardzija (0-2, 1.53), who has yet to yield more than two earned runs, can't seem to catch a break. The right-hander has struck out 27 and walked nine over five starts spanning 35 1-3 innings while receiving a combined nine runs of support.
Samardzija was in line for the victory before the Cubs (8-16) allowed five runs in the ninth inning in Wednesday's 7-5 loss to Arizona. He gave up two runs and seven hits in 7 1-3 innings.
"I'm going out and doing my job. As a starting pitcher, you know when you're pitching every fifth day and you come out - you have to have a short memory," Samardzija told MLB's official website. "You start carrying over start to start, that's when it starts to snowball on you. You keep doing your work and competing for the team and hope for the best."
Samardzija has received an average of 2.60 runs of support during an 11-start winless stretch dating to last year.
"He's doing what he's supposed to do," catcher Welington Castillo said. "He's giving us a chance. We just have to score a couple runs for him. I think he's been throwing the ball really good. ... He wants to compete, he wants to win. He wants the ball in every situation."
Samardzija surrendered three runs - one earned - and struck out seven in as many innings against the Reds earlier this month, dropping to 0-4 with a 4.75 ERA in his last seven starts in the series.
The Reds (11-14) suffered a three-game sweep at Atlanta to conclude a 5-5 road trip, falling 1-0 in 10 innings Sunday. Cincinnati lost 4-1 on Saturday and is 7 for 61 (.115) in its last two games.
"It was tough for us," Price said. "It was another one-run game that we weren't able to pull out. You want to win the games that are there."
The Cubs had dropped four in a row before posting their first shutout in Sunday's 4-0 win at Milwaukee. Starlin Castro went 3 for 4 with a pair of solo homers and Jason Hammel pitched into the eighth inning.
The Cubs dropped the three-game set to extend their string of winless series to 13. Chicago's last series win came at Cincinnati from Sept. 9-11.
However, the Reds are 25-7 against the Cubs dating to August 2012 after taking two of three in this season's first series.