Converging evidence supported that melamine could impair learning and memory and hippocampal function by mechanisms as yet unknown. Our aim was to obtain the first clues of how melamine affected spatial cognition, and how it may act on hippocampal function to modulate plasticity. Morris water maze test was used to probe spatial learning and memory. Pharmacological approaches were employed to modulate NMDAR and AMPAR-dependent long-term synaptic plasticity of rats’ hippocampal CA1 region. Both systemic and intrahippocampal application of melamine impaired the formation of long-term spatial memory, particularly consolidation memory. The reduced expression of NMDA-NR1 and -NR2B subunits, but not AMPAR subunits, was presented. Meanwhile melamine inhibited inductions of long-term potentiation (LTP) and long-term depression (LTD) via mediating NMDARs. Notably, the specific role of hippocampal CA1 LTD in regulation of spatial consolidation has been observed in normal physiology. Moreover, the prevention of inhibited hippocampal CA1 LTD but not LTP could rescue the disruption of long-term spatial memory of the melamine-treated rats. Taken together, our findings suggested that acute melamine exposure impaired spatial memory consolidation via disrupting hippocampal NMDAR-dependent LTD. This provided an important insight into the neurophysiology of melamine-related and other psychiatric disorders.