Gavin Lux also went deep for the Reds, who have won two straight and 11 of 16.
Aaron Judge accounted for the Yankees’ run with his 28th homer. Cody Bellinger had three hits.
It was only the second time in 14 games that Yankees pitchers allowed three or more earned runs. New York came in with a 1.99 ERA since June 10.
Cincinnati grabbed the lead with three runs in the fourth inning. De La Cruz, who had three hits, drove an RBI triple over Bellinger’s head in center field to tie it at 1 before scoring the go-ahead run on Spencer Steer’s sacrifice fly.
Lux followed with a solo shot to right off starter Allan Winans (0-1), called up from the minors to make his Yankees debut.
De La Cruz added an RBI single with the bases loaded in the fifth and a homer to right leading off the eighth.
Judge hit his fourth home run in 11 games against the Reds with a towering drive into the upper deck in left field in the first off starter Nick Lodolo.
Scott Barlow (3-0), the second of five Cincinnati pitchers, threw 1 2/3 scoreless innings for the win.
New York went 0 for 12 with runners in scoring position.
Jasson Domínguez singled to start the Yankees fifth, but then Cincinnati right fielder Jake Fraley made a leaping grab against the wall to rob Paul Goldschmidt of a hit.
De La Cruz is batting .309 with six home runs and 12 RBIs in June. That includes a 7-for-17 run in the last four games with two homers and two RBIs.
Cincinnati right-hander Chase Burns, the second overall pick in last year’s amateur draft, makes his big league debut Tuesday night. LHP Carlos Rodón (9-5, 3.10 ERA) goes for the Yankees.
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