Gonzaga remained unbeaten in three conference games and is 13-2 overall. Karnowski dominated inside with nine rebounds and blocked seven shots for a career high.
The Bulldogs built on a 14-point halftime lead and shot 49 percent from the field.
St. Mary's (10-4, 1-1 WCC) opened the season with nine straight wins, but has now lost four of five. The Gaels are playing without Coach Randy Bennett, who is serving a five-game suspension for a violation of recruiting rules.
Beau Levesque scored 12 points for St. Mary's, which attempted 12 shots from 3-point range and made just one of them.