Joey Votto drove in three runs with a two-run single and a RBI ground out.
Salazar (1-2) allowed seven runs, six earned, in 3 1/3 innings.
The outing was a setback for Salazar, who is trying to earn a spot in the Indians rotation.
"He started out with a solo home run in the first, then one in the second. Things got away from him," Indians manager Terry Francona said.
"The results haven't been there not yet. He's still young in age and in innings. The stuff is there."
Michael Lorenzen (2-0), who is competing for a spot on the opening day roster, made his first start for the Reds. He allowed four hits in three innings.
"My fastball command was good. My tempo was good," Lorenzen said. "I gave up hits on two-strike breaking balls. I wasn't finishing them. I made an adjustment and they were better in the bullpen."
Lorenzen threw 20 more pitches in the bullpen after his outing. He needs to be stretched out in case the Reds decide to use him to start in early season games.
"He has a good breaking ball," Reds manager Bryan Price said. "It would have been better used earlier in the count. It's a matter of time until he has confidence to finish them with two strikes."
Mesoraco and Hamilton had two hits. Chris Dominguez went 3 for 5.
Veteran Paul Maholm, competing for a role in the Reds' bullpen, pitched three scoreless innings.
"Maholm knows how to change speeds," Price said. "He knows how to create the kind of action he wants on the ball."
Reds: Homer Bailey pitched in a minor league game today. He will likely start the season on the disabled list. ... Johnny Cueto has arrived from the Dominican Republic where tended to a relative who was ill. ... He will pitch in a minor league game in his next to last start.
Indians: Jason Kipnis, who had been dealing with lower back tightness, played against the Reds on Thursday. Michael Brantley has a tight back and will be held out a couple of games. Nick Swisher continues to progress and is taking at-bats in minor league games.
Reds: Michael Lorenzen was a competitive lottery round pick (38th overall) in the 2013 draft. The 23-year old was a center fielder and closer at Cal State Fullerton. He is being considered for a roster spot as the early season replacement for Homer Bailey and also for long relief.
"I feel good about my chances because I know the work I've put in," Lorenzen said. "To get a start this late is awesome. I'm grateful for the chance. It is out of my hands. They have treated me great. When you truly believe it is out of your hands, you just enjoy your time."
Indians: Danny Salazar struck out the side in the first inning, but allowed Todd Frazier's home run. He allowed seven runs, six earned, and six hits in 3 1/3 innings, including two home runs and two hit batters.
Salazar was disappointed in his outing.
"I was getting behind in the counts," Salazar said. "Physically I felt good. I lost my release point. I didn't want to walk anybody and I got hit. Now I felt like (bad). You could see it my fastball was up. My change-up was right down the middle, not good."
The Reds acquired first baseman Dan Johnson from the Houston Astros for a player to be named later. Johnson will report to the Reds' minor league camp in Goodyear. The Reds traded infielder Devin Lohman to the Philadelphia Phillies for a player to be named later or cash.
The Indians optioned C.C. Lee to Triple-A Columbus and re-assigned INF Audy Ciriaco, OF Destin Hood, INF Francisco Lindor, RHP Dustin Molleken, C Adam Moore, RHP Bryan Price and LHP Michael Roth to minor league camp.