Pryor ran for three TDs, and Smiley and Wilder added two apiece. Wilder finished with 106 yards rushing.
Florida State (1-0) scored on their first touch of the new season on Rashad Greene's 47-yard punt return just 89 seconds into the game.
EJ Manuel passed for 188 yards and a touchdown before retiring midway in the third quarter.
The Seminoles totaled 606 yards while holding Murray State (0-1), a Football Championship Subdivision school, to 156 yards.
Murray State managed 39 yards rushing against the Seminoles, who return most of the defensive unit that finished last season ranked fourth nationally in total defense.
Pryor sandwiched a pair of 1-yard scoring runs around an 18-yard TD and Wilder scored on runs of 1 and 9 yards. Smiley scored twice on 1-yard runs.
Murray State failed to capitalize on its first scoring threat when Jordan Benton's 35-yard field goal try sailed wide left. Benton did connect later in the second quarter on a 28 yard kick to pull the Racers to within 21-3. And that was it.
It was Florida State's third win over a FCS school in any many seasons under coach Jimbo Fisher. The combined margin: 190-19. The Seminoles play another FCS team next Saturday when Savannah State visits.
Dustin Hopkins, who is on pace to shatter both the school and Atlantic Coast Conference scoring records, added field goals of 28 and 30 yards and extended his string of successful consecutive point after kicks to 139. Hopkins now has 341 career points, 53 shy of the league and school records.
Senior defensive end Brandon Jenkins, who had a first quarter sack, suffered a bruised left foot in the opening half and did not return as a precaution.
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South Carolina coach Steve Spurrier told his players and coaches Monday night that he is retiring immediately, sources told ESPN.com.
Steve Sarkisian has been plagued of late by apparent substance-related circumstances, including arriving to team facilities appearing intoxicated Sunday, according to sources.
Florida Gators quarterback Will Grier has been suspended for the year after testing positive for a performance-enhancing substance found in a supplement, coach Jim McElwain announced Monday.
Former USC coach Pete Carroll said Monday that he's saddened by Steve Sarkisian's situation and he has reached out to his former assistant.
Ole Miss offensive tackle Laremy Tunsil will be eligible to return to action for the Rebels following Saturday's game against Memphis, sources told ESPN.com on Monday.
After a decades-long ban, Nevada Gaming Control granted approval for the state's regulated sportsbooks to offer wagering on the Heisman Trophy, with LSU's Leonard Fournette the early favorite.