Del Potro cruised to a 6-3, 6-2 win over Viktor Troicki of Serbia and Querrey beat fourth-seeded Nicolas Almagro of Spain 6-2, 6-3.
American Querrey, ranked 36th, fired 10 aces in beating the 19th-ranked Almagro to reach his fifth ATP semifinal, his first since July.
Playing with confidence behind a powerful and accurate serve, Querrey took chances in return games, capturing breaks in the first and ninth games of the first set and the sixth and eighth games of the second.
"That (first) game set the tone for the rest of the match, so fortunately I won it,'' he said. "I'm going out and trying to be aggressive. This is the best I've played in a long time.''
Querrey will face another Spanish player, second-seeded David Ferrer, in Friday's semifinals. Ferrer advanced on a walkover when defending champion Philipp Kohlschreiber withdrew because of a shoulder injury.
Kohlschreiber played with the help of painkilling injections in his second-round match on Wednesday but informed tournament organizers Thursday he could not continue.
"It was not easy to make the decision,'' the German said. "Everyone likes to play in the quarterfinals and the tournament is just getting interesting so it makes me very sad.''
Del Potro broke Troicki in the second game and held serve to take the first set in 42 minutes. He broke the Serb in the first and third games of the second set but lost his serve in the sixth game before clinching the set in 41 minutes.
Del Potro will play the third seeded Sweden Robin Soderling in Friday's semifinals after Soderling ended the run of American qualifier John Isner 6-4, 6-4 in 58 minutes.
"Tomorrow I will have a tough match for sure but if I play my game I can win so I have to be focused on my play,'' Del Potro said.
Isner won five straight matches at the tournament - three in qualifying and two in the main draw - before bowing out to Soderling. He will now travel to Melbourne for next week's Australian Open where he has wild-card entry to the main draw.
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