Kainate receptors (KARs) are heteromeric ionotropic glutamate receptors that play a variety of functions in the regulation of the activity of synaptic networks. Little is known about the regulation of the function of synaptic KARs in the brain. In the present study, we found that a conditioning activation of synaptic NMDA receptors (NMDARs) induces short-term depression of KAR-EPSCs but not of AMPA receptor-EPSCs at synapses between mossy fibers and CA3 pyramidal cells. Short-term depression of KAR-EPSCs by synaptic NMDARs peaked at 1 s and reversed within 20 s, was likely induced and expressed postsynaptically, and was homosynaptic. It depended on a rise of Ca2+ in the postsynaptic cell and on the activation of the phosphatase calcineurin that likely binds to the GluR6b (glutamate receptor subunit 6b) subunit splice variant allowing the dephosphorylation of KARs and inhibition of activity. Finally, we show in the current-clamp mode that short-term depression of KAR-EPSPs is induced by the coincident discharge of action potentials in the postsynaptic cell together with synaptic stimulation. Hence, this study describes a form of short-term synaptic plasticity that is postsynaptic, depends on the temporal order of presynaptic and postsynaptic spiking, and likely affects the summation properties of mossy fiber EPSPs.