Ramirez hit a two-run homer in the first inning off Tyler Mahle (7-7) and connected for a three-run shot in Cleveland's nine-run third. With the Indians up 17-0, the All-Star was replaced in the fifth inning by manager Terry Francona before he could inflict further damage.
Francisco Lindor added a three-run homer and Jason Kipnis homered as the Indians salvaged the interleague series finale by pounding their neighbors from southern Ohio and ending a four-game slide.
It was a much-needed rebound by the AL Central leaders, who squandered a 4-0 lead in the ninth on Tuesday night, when Francona's miscommunication with pitching coach Carl Willis on a choice of relievers helped the Reds rally for seven runs and stun the Indians.
Carlos Carrasco (10-5) reached 1,000 career strikeouts, and given the humongous lead, coasted through five innings for his second straight win since coming off the disabled list. Adam Plutko worked four innings for his first career save.
Jesse Winker and Scooter Gennett homered for the Reds.
With 27 homers, Ramirez tied irascible slugger Albert Belle for the most in Cleveland history before the All-Star break, and the AL's starting third baseman in the midsummer classic has four games to make the record his own.
He's also just two homers shy from his entire total in 2017, and there doesn't seem to be anything out of reach for the 25-year-old Ramirez, who has emerged as one of baseball's most unlikely superstars.
Ramirez's second homer capped Cleveland's nine-run outburst in the third, giving the Indians a big lead that even their suspect bullpen couldn't squander.
The Indians' second nine-run inning this season helped take a little sting out of Tuesday night's late-inning meltdown, which Francona said kept him up awake most of the night.
Lindor connected in the fourth for his 25th homer. The Indians said Ramirez and Lindor are the first pair of players under 25 to hit at least 25 homers before the All-Star break.
Reds third baseman Alex Blandino made his major league pitching debut in the eighth. He allowed one hit and struck out two.
Reds: RHP Homer Bailey (right knee), who has been on the disabled list since June 2, will make two more rehab starts with Triple-A Louisville. Bailey has made five rehab appearances, including four starts. After one relief appearance, general manager Nick Krall said the team decided it was ''best if we left him as a starter,'' and that Bailey will rejoin the Reds' rotation when he completes his rehab stint.
Indians: LHP Andrew Miller threw 39 pitches off the Progressive Field mound, a significant step in his recovery from knee inflammation. The club's top reliever has been out since May 26. Next for Miller is facing hitters, and the Indians hope to have the left-hander match up with some minor leaguers this weekend before they consider activating him after the All-Star break.
Reds: Following an off day, RHP Matt Harvey opens a three-game series in St. Louis against right-hander Carlos Martinez. Harvey has been something of a good luck charm as Cincinnati was just 8-27 before he was acquired on May 8.
Indians: In a matchup of two of baseball's best, Corey Kluber (12-4) starts the opener of a four-game series against New York and Yankees ace Luis Severino (14-2). Kluber is 5-1 with a 1.80 ERA in seven career regular-season starts against the Bronx Bombers.