Pelfrey (6-9) lasted just four innings, giving up seven runs on eight hits, striking out five without a walk.
The Astros took the early lead, after George Springer returned from the disabled list by leading off the game with a base hit. He came around to score when Carlos Correa grounded out, giving the Astros a 1-0 lead after the first.
Houston tacked on two more in the second thanks to a two-run shot from Colby Rasmus.
Things went from bad to worse for Pelfrey and the Twins. The Astros loaded the bases with no one out in the fourth inning. Pelfrey struck out Rasmus and Luis Valbuena, but then Hank Conger hit a grand slam to make it 7-0.
Meanwhile Astros pitcher Collin McHugh scattered seven hits through 7 2/3 innings. He didn't allow a run and struck out six.
The Twins will hope to put an end to their two-game skid on Saturday when they send Ervin Santana (3-4) to the mound against Astros starter Lance McCullers.