Southern rallied from a 14-0 deficit midway through the first quarter, outscoring Grambling 38-19 the rest of the way.
Jaguars quarterback Dray Joseph threw five touchdown passes in the win.
His counterpart, DJ Williams accounted for three touchdown passes for the Tigers.
The win is a sweet send-off to a sour season. The Jags' end the year with a disappointing 4-7 record.
Grambling meanwhile, is searching for answers to a nightmarish 2012. The Tigers finish the season 1-10.