Quarterback Andre Broadous rushed for 54 yards and passed for 113 more to lead Cal Poly. The Mustangs cut the margin to two points on a 50-yard halfback reserve pass by Ryan Taylor to Willie Tucker with 1:34 to play. But Sam Houston's Trey Diller recovered the on sides kick attempt and the Bearkats ran out the clock.
Keshawn Hill scored the game's only touchdown on an 18-yard pass from Brian Bell with 0:31 left in the third quarter to end a nine-play, 83-yard drive.
After trailing 8-0 at halftime after two Antonio field goals and a safety on a punt block by Vincent Dotson, Cal Poly scored on fields goals of 23 and 27 by Bobby Zalud at the 9:34 and 3:88 mark in the third.
The Cal Poly defense limited Sam Houston to its lowest total offense of the season as the Bearkats gained 153 yards rushing and passed for 88 for a total of 241 yards.
Sam Houston's defense gave up 387 total yards but created three big turnovers including fumble recoveries by Kenneth Jenkins and Darnell Taylor, an interception by Robert Shaw and Dotson's punt block.
Flanders, with his 101 yards rushing, became the first back in 18 game to gain more than 100 yards against the Cal Poly defense. Chance Nelson led SHSU receiving with three catches for 38 points. Trey Diller returned four kickoffs for 53 yards, a punt for 14 yards and caught two passes for 16 yards.
Sam Houston, which reached the finals of the FCS playoffs last year, advances to the quarterfinal against Montana State. The Bulldogs won their second round game over Stony Brook 16-10.
In other playoff action, Illinois State defeated Appalachian State 38-37 in overtime, Georgia Southern topped Central Arkansas 24-16, Wofford downed New Hampshire 23-7, and Old Dominion won over Coastal Carolina 63-35.