The specific impact of propofol on memory consolidation remains controversial. Matrix metalloproteinase-9 (MMP-9) has been shown to be critical for modulation of long-lasting synaptic plasticity that is necessary for memory consolidation. We therefore sought to examine whether post-training propofol affects Morris water maze performance and subsequent MMP-9 expression in the hippocampus. Our results indicate that post-training administration of 150 mg/kg propofol but not 75 mg/kg propofol disrupts spatial memory retention 24 h after training. In addition, Morris water maze training induced a gradual increase in levels of pro-MMP-9 and active-MMP-9, which were attenuated by 150 mg/kg propofol but not 75 mg/kg propofol treatment immediately after training. Collectively, these findings indicate that the amnesic effect of propofol stems at least partially from its impairment of memory consolidation, which parallels with reduced activity of hippocampal MMP-9.