Bridgewater was 23-for-32 passing and hit DeVante Parker for two scores in the Cardinals (2-0) second lopsided win in a row.
John Wallace kicked three field goals for Louisville and Senorise Perry carried the ball 13 times for 37 yards and a 5-yard touchdown.
Louisville ran up 475 yards of total offense while the defense limited Eastern Kentucky (1-1) to 206 yards and kept the Colonels off the scoreboard until the fourth quarter.
Jared McClain hit Devin Borders for a 15-yard score with Louisville leading 37-0. McClain finished with 85 passing yards and was intercepted once.