Carreno Busta defeated Hubert Hurkacz 3-6, 6-3, 6-3 in last year's Canadian final in Montreal to capture the first Masters 1000 title of his career.
But a nagging injury has seen him play just four matches this season, most recently a three-set defeat to France's Richard Gasquet in Rotterdam in February.
Kyrgios, meanwhile, missed Wimbledon and his title defence in Washington this week with a wrist ligament injury.
Organizers said Shapovalov, who made it to the round of 16 at Wimbledon, pulled out because of a knee injury.
In a statement released by organizers the home hope said he had been "doing everything possible" to be fit for the tournament but the injury "needs more time."
As a result of the withdrawals, organizers said, Finland's Emil Ruusuvuori, American J.J. Wolf and Japan's Kei Nishikori will have automatic entry into the main draw.
The hard court tournament, one of the key tune-ups for the US Open starting at Flushing Meadows on August 28th, had already lost world number two Novak Djokovic.
The 23-time Grand Slam champion, who fell to Spain's Carlos Alcaraz in the Wimbledon final, withdrew on Sunday citing fatigue.
