EJ Manuel passed for 188 yards and a touchdown before retiring midway through the third quarter.
Murray State's Casey Brockman passed for 117 yards but was intercepted once and sacked six times, including four by Bjoern Werner.
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 ranked fourth nationally in total defense last season.
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 on a 28 yard kick later in the second quarter to pull the Racers to within 21-3. And that was it.
It was Florida State's third win over an FCS school in as many seasons under coach Jimbo Fisher. The combined margin: 190-19. The Seminoles play another FCS team next week when Savannah State visits.
Manuel had a streak of 128 consecutive passes without an interception snapped when Murray State's Josh Manning snatched a ball bobbled by Florida State receiver Kenny Shaw.
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 sack in the first quarter, suffered a bruised left foot in the opening half and did not return as a precaution.