Yadier Molina hit an RBI double and Ryan Helsley got Josh Fuentes to ground into a game-ending double play with the bases loaded. St. Louis completed a three-game sweep and has won nine of 11 overall.
Colorado dropped to a major league-worst 2-14 on the road.
Arenado was acquired from the Rockies in a blockbuster trade in early February after the star third baseman spent the first eight years of his career with Colorado.
He said it felt strange playing against his old teammates during the weekend series.
''It was definitely weird,'' Arenado said. ''Obviously, I know a lot of those guys. At the end of the day, it was a great series to win.''
Arenado has reached safely in 18 of the last 20 games. His mom, Millie, was in attendance on Mother's Day, which made the home run even more enjoyable.
He planned on taking Millie to dinner at a place of her choice later in the evening.
''It's just great to have moments like that with your family,'' St. Louis manager Mike Shildt said. ''That's what life is all about. These are magic moments that people will cherish for a long time.''
Wainwright (2-3) struck out five and walked three over 8 1/3 innings, improving to 11-1 against the Rockies. He retired nine batters in a row at one point and eight straight during another stretch.
The 39-year-old right-hander fell two outs short of his 11th career shutout. His last one came in 2016. The veteran simply keeps plugging along.
''I can't even tell you how much younger I feel than when I was 36, 37. It's just not even close,'' Wainwright said. ''I have a great time outperforming expectations.''
Molina and Wainwright have made 279 starts together as a battery, which ranks them sixth all-time.
''This guy amazes me every time he takes the mound,'' Molina said.
Helsley earned his second major league save and first this season.
Arenado homered leading off the second against German Marquez (1-4), who allowed two runs, one earned, in six innings. Marquez struck out six and walked three.
Molina added a run-scoring double in the fourth.
St. Louis improved to 14-4 since April 23, the best record in the majors during that span.
The Rockies have lost 22 games - 13 by two runs or fewer.
''There were a couple situational at-bats where we didn't get it done early in the game,'' Colorado manager Bud Black said. ''And then again we didn't get the big hit there in the ninth. We just couldn't cash in.''
Former St. Louis first baseman Matt Adams drew a standing ovation when he pinch hit in the eighth.
Wainwright committed just the fourth balk of his career in 333 starts. It came in the third inning. His last balk was on Aug. 1, 2014. ''It was a balk, no doubt about it,'' Wainwright acknowledged.
MOTHER'S DAY TRIBUTE
Molina wore special gear in honor of Mother's Day. He donned a pink chest protector and also wore white shin guards. His mother, Gladys, was in attendance. ''I'm happy for her,'' Molina said. ''She gets mad when we lose.''
Rockies: RHP Yency Almonte (0-1, 12.46 ERA) has been reinstated from the 10-day injured list. He had been out with right hand soreness. RHP Justin Lawrence was sent to Triple-A Albuquerque. ... INF C.J. Cron was held out of the starting lineup for the third successive game with back tightness. Cron, who is day to day, was scratched from the lineup on Friday.
Rockies: RHP Jon Gray (4-2, 3.12) will face San Diego RHP Dinelson Lamet (0-0, 0.00) in the first of a three-game series on Monday in Denver. Gray has allowed two earned runs or fewer in five of seven starts this season.
Cardinals: LHP Kwang Hyun Kim (1-0, 3.06 ERA) will face Brewers RHP Freddy Peralta (3-1, 3.38) in the first of a three-game set on Tuesday in Milwaukee. The Cardinals are 9-2 in games started by Kim in his career, including a 4-0 mark this season.
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