Castro continued his breakout campaign with his ninth home run of the season, one of three hit by the Cubs and one of seven on the night. Aramis Ramirez finished 3-for-5 and hit his 25th home run for Chicago, which has won three straight.
Rodrigo Lopez (5-6) gave up five runs on nine hits with four strikeouts and one walk over 5 1/3 frames, but it was good enough to halt a three-decision losing streak.
Dontrelle Willis (0-6) remained winless on the season after giving up eight runs on nine hits with three walks over 3 1/3 innings. The southpaw didn't strike out a batter for the Reds, who have dropped three in a row and six of nine. Brandon Phillips hit two home runs in the loss.
Leake, who reached the majors last season out of Arizona State, has alternated wins and losses in his last seven decisions, beginning with a 4-2 defeat against the New York Mets on July 25.
He got a no-decision in his last start, against the Cubs, after going nine frames in the Reds' 13-inning win on Sept. 6.
The 23-year-old is 3-1 lifetime against them with a 2.95 earned run average in 42 2/3 innings over six starts.
He's faced by 34-year-old righty Ryan Dempster, an ex-Red who was on the winning end of Leake's Aug. 5 loss, allowing two runs and four hits in a 4-3 triumph.
Dempster returned to face the Reds again in Sept. 7 and got a no-decision in Chicago's 4-3 victory after giving up 10 hits and three runs.
The British Columbia native hasn't won since Aug. 11, when he completed a three-start streak with a 4-3 triumph over Washington.
A Red for 37 games in 2002-03, Dempster is 7-7 against them in 41 career appearances.
Though the Cubs have won six of their last eight over the Reds, Cincinnati still leads the season series, 8-7.