Smith had a pair of short-yardage scoring runs in the second quarter. Douglas picked off Hasaan Klugh twice, and ran for 52- and 48-yard touchdowns in the first half. Parker Shaunfield kicked three field goals and Southern Miss (7-4, 5-2 Conference USA) led 38-7 at halftime.
Smith ran for an 80-yard touchdown in the third quarter, and finished with 153 yards. He has rushed for 100 yards or more in six games this season.
Klugh threw a touchdown pass and ran for another for Charlotte (1-10, 1-6).
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Two top-10 teams have not squared off at Notre Dame Stadium since 2005.
Central Florida looks to extend the nation's longest winning streak when it plays the second contest of a three-game homestand by hosting Pittsburgh on Saturday afternoon.