Wake Forest netted a pair of goals three minutes apart in the first half.
The Demon Deacons added their third goal in the 39th minute.
William and Mary recorded its lone goal on its first shot in the 52nd minute when senior Rachel Moore fed a cross to classmate Sami Grasso, who redirected it into the back of the net to cut the deficit to 3-1.
Wake Forest was picked to finish ninth in the competitive 14-team Atlantic Coast Conference that put six teams in the United Soccer Coaches NCAA Division 1 Preseason Top 25.
The host Indianapolis Colts lost 24-10 to the Detroit Lions Sunday as former William and Mary linebacker Luke Rhodes made two tackles for the Colts.