Antipsychotic-induced low availability of group II metabotropic glutamate receptors (including mGlu₂R and mGlu₃R) in brains of schizophrenia patients may explain the limited efficacy of mGlu_2/3R ligands in clinical trials. Studies evaluating mGlu_2/3R levels in well-designed, large postmortem brain cohorts are needed to address this issue. Postmortem samples from the dorsolateral prefrontal cortex of 96 schizophrenia subjects and matched controls were collected. Toxicological analyses identified cases who were (AP+) or were not (AP-) receiving antipsychotic treatment near the time of death. Protein and mRNA levels of mGlu₂R and mGlu₃R, as well as GRM2 and GRM3 promoter-attached histone posttranslational modifications, were quantified. Experimental animal models were used to compare with data obtained in human tissues. Compared to matched controls, schizophrenia cortical samples had lower mGlu₂R protein amounts, regardless of antipsychotic medication. Downregulation of mGlu₃R was observed in AP- schizophrenia subjects only. Greater predicted occupancy values of dopamine D₂ and serotonin 5HT_2A receptors correlated with higher density of mGlu₃R, but not mGlu₂R. Clozapine treatment and maternal immune activation in rodents mimicked the mGlu₂R, but not mGlu₃R regulation observed in schizophrenia brains. mGlu₂R and mGlu₃R mRNA levels, and the epigenetic control mechanisms did not parallel the alterations at the protein level, and in some groups correlated inversely. Insufficient cortical availability of mGlu₂R and mGlu₃R may be associated with schizophrenia. Antipsychotic treatment may normalize mGlu₃R, but not mGlu₂R protein levels. A model in which epigenetic feedback mechanisms controlling mGlu₃R expression are activated to counterbalance mGluR loss of function is described.