Metabotropic glutamate (mGlu) receptors mediate in part the CNS effects of glutamate. These receptors interact with a large array of intracellular proteins in which the final role is to regulate receptor function. Here, using co‐immunoprecipitation and pull‐down experiments we showed a close and specific interaction between mGlu₅ receptor and NECAB2 in both transfected human embryonic kidney cells and rat hippocampus. Interestingly, in pull‐down experiments increasing concentrations of calcium drastically reduced the ability of these two proteins to interact, suggesting that NECAB2 binds to mGlu₅ receptor in a calcium‐regulated manner. Immunoelectron microscopy detection of NECAB2 and mGlu₅ receptor in the rat hippocampal formation indicated that both proteins are codistributed in the same subcellular compartment of pyramidal cells. In addition, the NECAB2/mGlu₅ receptor interaction regulated mGlu_5b‐mediated activation of both inositol phosphate accumulation and the extracellular signal‐regulated kinase/mitogen‐activated protein kinase pathway. Overall, these findings indicate that NECAB2 by its physical interaction with mGlu_5b receptor modulates receptor function.