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.
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 past 20 games. His mom, Millie, was in attendance on Mother's Day, which made the home run even more enjoyable.
"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 8⅓ 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, 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 -- and dropped to a major league-worst 2-14 on the road.
"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."
The Associated Press contributed to this report.