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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A final decision in Ohio State's quarterback derby won't be revealed until just before the season kicks off, but Urban Meyer isn't ruling out playing both his decorated candidates.
Florida linebacker Antonio Morrison, who injured his left knee in January and needed two surgeries to repair the damage, will play in Saturday's opener against New Mexico State.
Middle Tennessee coach Rick Stockstill has named his son, redshirt freshman Brent Stockstill, his starting quarterback for the Blue Raiders' season opener against Jackson State.
A new college football award will be given to the nation's best offensive line and honor the memory of Joe Moore, who coached 52 players who went on to the NFL.
Miami has lost running back Gus Edwards for the entire season because of a left foot injury.
Virginia Tech will wear a decal on its helmets against No. 1 Ohio State on Monday night to honor slain Roanoke television journalists Alison Parker and Adam Ward.