Raonic, a runner-up in 2012 and 2013, came through a hard-fought encounter against the Uzbek world number 60 on Friday to progress 7-6 (10-8) 6-3.
In securing a third career win over Istomin from as many attempts, the Canadian third seed hit 15 aces in total and won all but one his 39 first service points.
Having seen the big-serving 23-year-old blow away Istomin, fourth seed Kei Nishikori was next through with a relatively straightforward 6-4 6-2 win over Jeremy Chardy.
The Frenchman accounted for seventh seed Kevin Anderson on Thursday but was unable to ensure another scalp at the ATP 500 hard court event.
Nishikori fought back from two games down in the first set and went on to save four of five break points to beat Chardy for the first time since 2011.
Home favourite Nishikori will meet Germany's Benjamin Becker next after he saw off American Jack Sock in the only match of the day to go to three sets.
Becker came from a set down to outlast Sock 4-6 6-1 6-4 - saving eight of nine break points in the process.
The last time US Open runner-up Nishikori faced Becker, the Japanese won through in Memphis and went on to win the National Indoor Tennis Championships.
Gilles Simon came through his first career meeting with Steve Johnson to set up a semi-final meeting with Raonic.
The world number 37 hit seven aces in total as he moved past his American opponent 7-6 (7-4) 6-1 in an hour and 29 minutes.