Nikki Moody had 15 points and 10 assists for the Cyclones (5-0).
Cara Lutes scored 19 points for the Bulldogs (1-4), who shot 16.1 percent (5 of 31) in the first half and went 11:40 without a field goal as Iowa State built a 51-13 halftime lead.
It was Iowa State's eighth win in the last nine games between the schools and tied the all-time series at 26 victories each. The winning margin of 42 points was bettered only by the 95-29 win (66 points) by the Cyclones in 1975.
Iowa State played its second game without star forward Chelsea Poppens, who suffered a concussion against Loyola Marymount on Nov. 23. She has plenty of time to rest before the team's next game against Iowa on Dec. 6.