The three-time grand slam champion missed out on glory at the Sofia Open, losing to eventual champion Mirza Basic in the semi-final on Sunday (AEDT).
And he was spectacularly humbled again on Tuesday by world number 259 Griekspoor, who claimed his first Tour-level win in only his third ATP match with a remarkable comeback.
Fifth seed Wawrinka needed just a sole break to take the first set and, with 246 places separating the two players in the rankings, a comfortable victory for the Swiss appeared on the cards.
But Dutchman Griekspoor delighted the home fans by moving into a 3-0 lead in the second before forcing a decider, which he subsequently dominated to record an astonishing 4-6 6-3 6-2 triumph.
Griekspoor did not face a break point after the first set and his triumph sets up the prospect of a potential quarter-final showdown with Roger Federer.
Wawrinka was not the only seed to crash out, as ninth seed Gilles Muller was defeated 6-4 7-6 (11-9) by qualifier Daniil Medvedev.
There was no such disappointment for David Goffin, a 6-1 6-3 victor over Nicolas Mahut.
Elsewhere in the draw, Viktor Troicki won in three sets against Jan-Lennard Struff, whose German compatriot Philipp Kohlschreiber beat Karen Khachanov in a match that went the distance.