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.
Nike Men's Florida State Seminoles Garnet/Gold Team Issue Performance PoloShop
The silence from LSU's administration this week about Miles' job status spoke volumes, but not as loudly as the support Tigers fans showed on Saturday. It's been a strange week in Baton Rouge.
Joe Mixon and Samaje Perine combine for 267 rushing yards and four touchdowns in Oklahoma's 58-23 victory over Oklahoma State that captured the Big 12 title for the Sooners.
Paul Harris ran 27 times for 166 yards and a touchdown to help Hawaii snap an eight-game losing streak on Saturday night, 28-26 over Louisiana-Monroe.
Check out the top plays from Week 13 of the college football season, including highlights from Baylor's loss to TCU, Ohio State beating Michigan and Les Miles' emotional win at Tiger Stadium.
The Capital One Cup Impact Performances of the Week include Stanford QB Kevin Hogan, Ohio State RB Ezekiel Elliott, Oklahoma QB Baker Mayfield and Alabama RB Derrick Henry.
Donnel Pumphrey and Chase Price surpassed 100 yards rushing on Saturday night, and San Diego State completed an undefeated conference season with a 31-14 win over Nevada.
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