Spikes set a school and Southland Conference record with 148 return yards as he picked off a pass in the first, second and fourth quarters.
The defense allowed the Cardinals past midfield once in the first half and two more drives ended in first-half turnovers. Shea Nutt picked off a pass to stop Incarnate Word's first drive and Wallace Scott forced a fumble, recovered by Cameron Smith, to thwart another.
McNeese State (5-2, 3-1 Southland) led 28-0 at the break. Dylan Long led the Cowboy offense with three touchdowns in the first half.
Scelfo finished with 254 yards passing for IWU (1-7, 1-4).