St. Louis won its season-high seventh straight in a slugfest that took 4 hours, 25 minutes - the longest nine-inning game in the majors this season.
DJ LeMahieu homered for the Yankees, who have lost five in a row. It's their worst skid since a seven-game slide last September.
St. Louis (60-48) moved a season-best 12 games over .500 with its first regular-season series sweep of the Yankees. The surging Cardinals moved two games ahead of second-place Milwaukee in the NL Central.
''Anytime you can cap off a sweep of a great team like the Yankees, it's huge,'' Arenado said. ''We beat a team that's playing great ball, too. Where we're trying to go, you've got to win series. It's just great to see us playing good baseball, playing hard.''
New York still has the best record in the American League but its lead in the AL East is down to 9 1/2 games over Toronto, the first time it's been single digits since June 15.
St. Louis became the first team to sweep the Yankees in a series of at least three games this year. Atlanta and the New York Mets are the only clubs in the majors to avoid that fate so far.
Arenado, who launched a three-run homer in the second inning, had three hits and leads the majors with 18 RBIs in interleague games this season.
DeJong, who broke a 6-all tie with a fifth-inning double, added a three-run drive in the eighth inning - his 100th career home run.
''I knew they weren't going to go down quietly after we beat them the first two games,'' DeJong said. ''Today was a great game, one of the most memorable games I've played here.''
DeJong also drove in the decisive runs in the eighth inning of Friday night's 4-3 win in the series opener.
''What DeJong did was pretty special,'' St. Louis manager Oliver Marmol said. ''It's good to see Paulie being Paulie.''
DeJong was sent to Triple-A Memphis on May 10 after a rough start to the season. He was recalled on July 30.
''I'm just thankful that I'm getting those chances,'' DeJong said. ''It's been so much fun since I've been back - just really enjoying every day here.''
Aaron Judge drove in four runs for New York, pushing his AL-leading total to 97 RBIs.
Frankie Montas struggled in his Yankees debut. Acquired from Oakland on Monday, the right-hander allowed six earned runs and five hits over three innings. He struck out two and walked three.
''I was not in sync with my mechanics. I was missing my spots a lot,'' Montas said. ''When you give that team a chance to hit those pitches, that's what's going to happen.''
New York manager Aaron Boone was ejected by plate umpire Ed Hickox in the fifth for apparently arguing balls and strikes. It was the 23rd ejection for Boone and his sixth this season. Pitching coach Matt Blake was also tossed. He was ejected by third base umpire Vic Carapazza.
Judge gave his team a 4-1 lead with a two-run single in the second. St. Louis responded with five runs in the bottom half. Arenado's 22nd homer put St. Louis up 6-4.
The Cardinals scored three times in the fifth to break a 6-all tie. Tommy Edman followed DeJong's double with a run-scoring hit. DeJong was originally called out at the plate on the play, but the call was reversed after a replay review.
St. Louis starter Adam Wainwright gave up four runs and eight hits over four-plus innings. He struck out five and walked four.
Aaron Hicks had three hits and reached base four times for the Yankees.
St. Louis completed a 6-0 homestand, its first homestand sweep of six games or more since September 2013.
Chris Stratton (6-4) picked up the win, allowing two runs over 1 2/3 innings of relief. He struck out four and did not walk a batter.
Ryan Helsley earned his 11th save in 14 chances.
Albert Abreu (2-1) took the loss.
Wainwright and C Yadier Molina made their 318th start together, second all-time behind the Detroit duo of Mickey Lolich and Bill Freehan (324) from 1963-1975.
BUSCH III KING
Molina got his 1,000th career hit at Busch Stadium III with a single in the third. He is the career leader at the stadium, which opened in 2006.
Yankees: 1B Anthony Rizzo sat out his third successive game with a back issue. He missed four games last month with back problems.
Cardinals: OF Juan Yepez will begin a rehab assignment Tuesday at Triple-A Memphis. He has been out since July 15 with a right forearm strain.
Yankees: RHP Jameson Taillon (10-2, 3.96 ERA) will face RHP Logan Gilbert (10-4, 3.09) in the opener of a three-game series Monday in Seattle. Taillon allowed six runs over 4 2/3 innings of an 8-6 loss to the Mariners on Tuesday.
Cardinals: RHP Miles Mikolas (8-8, 2.92 ERA) takes on Colorado RHP Ryan Feltner (1-3, 5.75) in the first of a three-game series Tuesday in Denver. Mikolas has allowed five home runs in three career starts at Coors Field.
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