The visitors dished out a 4-1 hiding at Dick's Sporting Goods Park, scoring twice in each half, before conceding a consolation goal to the Rapids later on.
Daniel Luduena fired home the opener in the 14th minute before Mexico international Oribe Peralta made it 2-0 just before the half-hour-mark with a simple tap-in from Ivan Estrada's cross.
Santos were in full control when Carlos Quintero added a third in the 64th minute before Christian Suarez wrapped up proceedings seven minutes later with a neat finish from the right side of the penalty area.
Brian Mullan pulled one back for the Rapids with just over ten minutes remaining but it was not enough to deny Santos a big win away from home which allowed them to go top of the Group B Table on six points from three outings.
The Rapids dropped to third following their first loss and will need a positive result against Honduran outfit Real Espana next week to keep their knockout stage qualification hopes alive.