The aim of the present study was to investigate and compare the effects of acute and chronic (21-day) administration of agonist (WAY-181187) and antagonist (SB-742457) of the 5-hydroxytryptamine 6 receptor (5-HT₆R) on MK-801-induced memory impairments in novel object recognition (NORT) and Y-maze continuous spontaneous alternation tests (Y-CAT). Further, the expression of the brain-derived neurotrophic factor (BDNF) in rat hippocampus was measured after 21-day administration to investigate BDNF participation in the pro-cognitive effects of 5-HT₆R ligands. We found that acute administration of WAY-181187, as well as SB-742457, reversed the effects of MK-801 in NORT and Y-CAT, and that this influence persisted after prolonged application in NORT but not in Y-CAT. Both 5-HT₆R ligands increased hippocampal BDNF protein expression, but WAY-181187 was much more potent than SB-742457 and alleviated the MK-801-induced inhibition of BDNF signaling pathways better, which seems to translate into a stronger WAY-181187 effect in behavioral tests. Collectively, both the 5-HT₆R agonist and the antagonist, administered acutely and chronically, prevent memory impairments and alterations in BDNF signaling induced by MK-801 in rats. The present results confirm the pro-cognitive properties of both types of 5-HT₆R ligands and suggest that BDNF pathways may be involved in their mechanism of action.