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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Will Grier threw four touchdown passes to four receivers -- all in the first half -- and No. 25 Florida downed third-ranked Mississippi 38-10 on Saturday night.
Leonard Fournette highlighted his SEC-record third straight 200-yard game with a 75-yard touchdown run, and No. 9 LSU overcame Eastern Michigan 44-22 on Saturday night.
An officiating error led to an Oklahoma State touchdown Saturday in the Cowboys' 36-34 win over Kansas State.
Texas A&M receiver Ricky Seals-Jones, who was ejected for targeting midway in the second quarter of Saturday's game, took to Twitter late in the game, retweeting a tweet that questioned the call.
Florida State running back Dalvin Cook exited in the first quarter of the Seminoles' 24-16 win over Wake Forest with a left hamstring injury. He is day-to-day.
As if things weren't going bad enough at Texas, the Longhorns appear to have players on Twitter during lopsided losses and jabs at their coach accidentally being sent from other nearby teams.