The Mariners rocked the righty for four runs in the third inning and six runs total in an 8-7 victory on Sunday afternoon in Minute Maid Park.
Seattle claimed the three-game set with the win, atoning for Houston's own series victory against the Mariners in April.
The Astros trailed 8-4 in the eighth but got a two-run single by Marc Krauss and scored another run in the ninth on a single by Jason Castro. But Seattle closer Danny Farquhar struck out Matt Dominguez to sew up a one-run decision in each of the series' three games.
McHugh had taken the league by storm with perhaps two of Houston's best starts this season in spot duty for the injured Scott Feldman. He locked down the Mariners and then came within an out of a complete-game shutout against the A's.
His 12 strikeouts on April 22 against Seattle were the second-best total in franchise history for a pitcher making his team debut. He was just the third pitcher in club history to win his first two games while striking out at least 19 hitters.
It all came to a screeching halt on Sunday.
The offspeed pitches McHugh had relied on for easy outs suddenly looked like softballs for the Mariners, who had him thoroughly scouted this time.
"What you saw today was a team make an adjustment, and [Collin] didn't have the sharpness to his breaking stuff like he had that day in Seattle," said Houston manager Bo Porter. "Those guys did a good job of backing the ball up. A lot of those big hits were the other way."
The hits just kept coming, including five in the decisive third inning. McHugh had allowed just five hits in the first two starts combined.
Each of the first four hitters in the Mariners lineup collected at least one RBI, with Willie Bloomquist and Robinson Cano responsible for the first four as Seattle jumped to a 6-1 lead.
McHugh was done after a whopping 85 pitches in just four innings, bumping his ERA from 0.59 to 2.79.
"You're tired obviously after an inning like that," McHugh said. "It's tough to come back and get on top of them when you throw [35 pitches] at once."
Prior to Sunday, Porter said McHugh had "earned his keep" and general manager Jeff Luhnow said he saw McHugh in the team's plans this season after his inaugural gems.
That may be in jeopardy after McHugh looked more like the pitcher who compiled an 0-8 record and an 8.94 ERA in 15 Major League games before joining the Astros. Though Scott Feldman could return by Friday, McHugh said he's not worrying about his place on the team.
"I'll leave that up to the coaches," McHugh said. I don't worry about [my standing]. I can't control it."
Like they did after the Mariners posted an eight-run inning on Saturday, the Astros struck back immediately to keep the outcome in doubt.
"We've been really resilient of late," said Alex Presley, who started for the fourth game in a row and went 2-for-3 with a solo homer.
It was Chris Carter doing the damage again, as he delivered a two-run double off the left-field wall to drive in Presley and George Springer in the fourth.
Carter's power surge against Seattle hasn't let up. He now has seven home runs and 18 RBIs against the Mariners over the past two seasons. Along with the double and a 430-foot triple Saturday, his slugging percentage versus the Mariners is above .1000 during that span.
Jonathan Villar added a solo shot in the fifth for his second home run in as many days. He now has a team-leading five long balls and his 14 extra-base hits this season lead all American League shortstops.
"He's taking his craft serious," Porter said. "His preparation is vastly improved, and his BP is better. He's strong enough to put some backspin on the ball and get some out of the park."
A comeback was in the works in the eighth inning, as Krauss capped off three consecutive hits with a two-run double with nobody out to make it 8-6. The threat fizzled when Springer and Carter each flew out to deep right field before Marwin Gonzalez struck out.
The Astros posted a season-high 11 hits in each game this series and recorded back-to-back multi-homer games, giving them 10 on the season, good for third in the AL. Houston scored 20 runs in the series, a season high.
That offensive improvement will be tested with Max Scherzer and the Tigers up next.
"We're putting stuff together and we're as confident as we've been all year, so we're looking forward to the challenge," Presley said.
The Astros finished a season-long 11-day homestand with a 3-6 mark, losing two series and splitting a four-game set with the A's. Houston's next seven games and 17 of its next 23 are on the road.