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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Florida State coach Jimbo Fisher hopes quarterback Sean Maguire is ready to go full speed by the middle of June.
Graduate transfer quarterback Davis Webb has officially joined California, giving the Golden Bears an experienced option to replace No. 1 overall NFL draft pick Jared Goff.
First-year football coach Dino Babers, hired by former Syracuse AD Mark Coyle, is on the committee that will search for Coyle's replacement.
Hugh Freeze has some major holes to fill on offense with the departures of Laremy Tunsil and Laquon Treadwell, but there is Chady Kelly and good depth.
After transferring in from Montana State, Dakota Prukop has a checklist he's working from as he prepares to compete for the Oregon job.
The destination for Week 6 of the Big 12 Ultimate Road Trip is unanimous, as all three conference reporters would head to the Red River Rivalry.
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