Isaiah Canaan scored 15 points and Donte half run to open its NCAA 41 victory over Colorado State.
The Racers (31-1), champions of the Ohio Valley Conference, were rewarded for an incredible season with a sixth seed in the West Region and will next take on the winner between Marquette and BYU in Saturday's third round.
Murray State won its first 23 games and was the last unbeaten team in the nation before suffering its lone loss of the season against Tennessee State in early February. The Racers followed that setback with seven more wins and beat Tennessee State twice during that span, including a narrow 54-52 win in the final of the OVC Tournament.
Pierce Hornung scored 12 points and grabbed 17 rebounds for Colorado State (20-12), which earned an at-large berth out of the Mountain West Conference. Jesse Carr chipped in 11 points in defeat for the Rams.
Colorado State carried a 24-23 lead to the break, but Murray State immediately took control at the start of the second half with an 18-2 run.