The seventh seeded del Potro, who won this ATP Tour event in 2011, beat American wild card Querrey 7-5, 7-5 in a 93 minute match on Stadium Court.
The Argentinian hammered eight aces, had two double faults and won 87 percent of his first serves points while overcoming 16 aces by Querrey.
De Potro has split his two career meetings with Raonic, but they haven't played in four years.
"It's going to be a big chance for me," said del Potro. "He's the favorite and is playing so good, but I want to see how my level is against the top players at this part of the year."
Little separated del Potro and Querrey during their quarter-final match, but the Argentinian gained the lone break in each set at 5-5. He denied Querrey any break point chances.
Del Potro reached the semi-finals of this event last year before going on to win 32 matches and being named the Tour's comeback player of the year for the second time.
The 28-year-old Argentinian, who won the 2009 US Open title, has endured three left wrist and one right wrist surgeries in his career.
Raonic book semi-final place
Meanwhile, Raonic booked his semi-final berth by rallying to beat Britain's Kyle Edmund 4-6, 6-3, 6-4.
The 26-year-old hard-serving Canadian blasted 10 aces and won 90 percent of his first serve points against eighth-seeded Edmund in their first-career meeting.
The turning point in the 99 minute match came early in the third set after the pair split the first two sets. Raonic hit a monstrous forehand return winner during Edmund's first service game of the final set. Raonic's confidence grew and Edmund's level declined after that.
Raonic, who is making his Delray Beach debut, grew frustrated at one point in the second set slamming his racquet on the ground as he fought to get back into the match after dropping the first. It marked the first time Raonic had dropped a set this week.
Raonic, who was forced out of the Davis Cup with the thigh injury he suffered during the Australian Open in January, has shown no ill effects.
He is coming off his best career season in 2016 when he finished the year ranked third in the world.
The other semi-final has been set, with third-seeded Jack Sock downing fifth-seeded fellow American Steve Johnson 6-4, 7-6 (7/4) to book a meeting with unseeded Donald Young.
Young advanced by walkover when Belgian Steve Darcis pulled out to attend to family matters.
Sock, the highest-ranked American men's player at No. 21, is going after his second title in 2017. He has yet to lose a set on a hard court this year and has a 10-1 match record.