Dunn homered in the first, Lopez went deep in the third, and Kearns hit one out in the eighth.
Milton (2-0) allowed three runs -- two earned -- in 6 2/3 innings in his second solid outing of the season. He left after retiring pinch-hitter Todd Walker and Juan Pierre to start the seventh. Todd Coffey relieved him and struck out Jerry Hairston Jr.
Milton also tripled with one out in the fifth and scored his second run of the game on an errant pickoff throw by Carlos Zambrano that increased the Reds' lead to 5-1 and left Cubs manager Dusty Baker shaking his head.
The way Milton was pitching early on, Chicago couldn't afford miscues.
Matt Murton hit the first pitch of the fourth inning over the center-field wall for his second home run, and the Cubs scored two more in the fifth on Murton's bases-loaded single and Dunn's error in left.
Otherwise, Milton kept them in check.
"Guys came in before the game and said the wind is blowing out, but you can't really think about it," Milton said. "There were some deep fly balls, but fortunately, only one got out. I'll take that."
The Cubs weren't as fortunate.
Zambrano (0-1) allowed five runs (four earned) on four hits, walked three, hit a batter and struck out eight in his third start of the season and second shaky outing against the Reds. He allowed five runs and walked five in 4 2/3 innings but didn't figure in the decision in the Cubs' 16-7 win at Cincinnati on opening day.
After allowing two unearned runs in six innings in his last start against St. Louis, Zambrano got into trouble early.
Dunn went deep with two out in the first, sending a 1-0 pitch to the left-field bleachers for his fifth home run of the season and third of the series. He hit two of the Reds' six homers in Tuesday's 9-2 victory.
"His command was a little off today," Lopez said. "I was just concentrating on getting a good pitch to hit. ... I was trying to hit the ball hard in the gaps."
Zambrano has allowed 12 walks after issuing 86 in 33 games last season.
"I hate them," he said of the free passes. "I have to be able to control them and throw more strikes."
The focus he had against St. Louis simply wasn't there. The same goes for the rest of the team.
After sweeping a three-game series at home over Cardinals, the Cubs dropped two of three against the Reds to finish 4-2 on the homestand.
"I don't think that we should be satisfied," Derrek Lee said. "We played decent, but I felt like we kind of let down after the big St. Louis series. That happens, but we can't allow that to happen because it'll catch up to you."
Both teams were missing key players.
The Reds kept Ken Griffey Jr. out of the lineup as a precaution after he left Wednesday's game with stiffness in the back of his right knee.
With the bases loaded and two out in the fifth, Murton singled to left to drive in Henry Blanco and Dunn bobbled the ball, allowing Zambrano to score from second to make it 5-3.
Kearns made it 8-3 in the eighth when he hit Bob Howry's first pitch of the game over the right-field wall for his third homer of the season.
"Mentally, we just didn't get it done for whatever reason," Pierre said. "Stuff went our way a couple times in the Cardinals series, and this time we didn't put ourselves in a position to have things go our way."
- Baker hopes to have Ramirez available for this weekend's series at Pittsburgh but might hold out Jones until the three-game set against the Dodgers in Los Angeles. "(Jones) will probably want to play, but I'll have to analyze it," Baker said. Both players were injured in Tuesday's game. Baker said Ramirez is "feeling better. Hopefully, he'll be all right by Pittsburgh. At this juncture of the season, we want him to feel great."
- Griffey said he was available to pinch-hit. "It's just a little tight," he said. "I'll get some treatment and see how I feel tomorrow (Friday)."
- One day after Edwin Encarnacion committed three of the team's five errors, Rich Aurilia started at third for the Reds.