Back in the green and gold for the first time in almost two years, Stosur made a shaky start, framing two forehands to drop serve in the opening game of the match.
She hit straight back, though, firing a nerve-settling off-forehand winner before two double-faults and a backhand error from Kerkhove allowed Stosur back on level terms.
A ferocious backhand return winner earned Stosur a second break in the fourth game and Australia's most prolific Fed Cup singles winner appeared to be up and running.
But half an hour and a bagful of unforced errors later, Stosur found herself a set down.
Typically, it was an overcooked forehand from Stosur that handed Kerkhove the set.
Australia's former grand slam champion steadied in the second set, holding serve for four successive games only to rue a huge opportunity lost after blowing three consecutive break points while leading 4-3.
Instead of being presented with a chance to serve out the set, Stosur was forced into a tiebreaker – and the little-known Kerkhove seized the moment to score the biggest win of her career.
"It's an amazing feeling. I'm really happy about this match," Kerkhove said after clubbing 21 winners to Stosur's 10.
"Sam is a great player and the way I played today was the only way I could win."