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.
Major League Baseball
The MLB Postseason is now underway. Follow the race to the World Series with Flashscore!
MLB news and updates | Postseason fixtures and results | Complete guide to the Postseason