De La Cruz, 24, brought in catcher Tyler Stephenson with a base knock to left field as the Reds broke their three-game losing streak.
He finished the game going 2-for-4 after going 0-for-4 in the first game of the doubleheader, which the Reds lost 2-1.
The Reds' walk-off win comes after Dane Myers tied it with a blast with two outs in the bottom of the ninth inning.
It was his second home run during the doubleheader, with this one helping the Reds to a win, bringing his season total to five.
De La Cruz is slashing .261/.344/.475 with 20 home runs, 57 RBI, and 21 stolen bases through 106 games this season. He needs just six more home runs to set a new career high.
The two-time All-Star can also set a career best if he finishes the season with a batting average better than .264. Both his on-base percentage and slugging percentage are already personal bests.
The Reds currently sit in last place in the National League Central division with a 60-65 record. They sit 6.5 games back of a Wild Card spot with 37 games left in the season.
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