Lactate is an important metabolite produced by astrocytes and delivered to neurons to support their energy needs in a process known as the astrocyte-neuron lactate shuttle. Emerging research during the past decade has unveiled a role of lactate as a signal capable of orchestrating critical functions ranging from neuroprotection to memory. In previous work, we found that lactate enhanced the amplitude and decay time of NMDA receptor currents (INMDAR) evoked by brief applications of glutamate and glycine. These effects were not observed when neurons were exposed to lactate receptor (HCA1) agonists. In contrast, inhibition of lactate transporters (MCTs) or lactate dehydrogenase (LDH) prevented lactate-mediated increases in INMDAR amplitude. Here, by using whole-cell patch clamp techniques on primary cortical neurons, we delve deeper into the pathway underlying lactate-induced INMDAR potentiation. We found that manipulating the intracellular and extracellular redox balance additively influenced INMDAR. Moreover, chelating intracellular Ca2+ or blocking ryanodine receptors (RyRs), a group of intracellular calcium channels modulated by redox changes, prevented the lactate-induced potentiation of INMDAR. Consistent with elevations of cytosolic Ca2+, intracellular infusion of specific CaMKII peptide inhibitors also abolished the potentiation of peak INMDAR responses by lactate. These results indicate the existence of a mechanism that requires entry of lactate into neurons, redox changes via lactate oxidation to pyruvate, Ca2+ release from intracellular stores, and involvement of CaMKII. Together, these insights refine our understanding of how lactate modulates INMDAR and establish a link between lactate metabolism and glutamatergic-dependent synaptic plasticity.