Chronic social stress induces emotional and cognitive disturbances and is a risk for mental illness. Reduced neuronal activity in the medial prefrontal cortex (mPFC) underlies these behavioral abnormalities. However, the subcellular origin and process of this neuronal change remain elusive. Here we examined ultrastructural and multi-omics changes in the mPFC with social stress in mice. Social stress caused the loss of dendritic branches with morphological alterations of mitochondria and induced synaptic shrinkage selectively at mitochondria-containing synapses. Social stress deteriorated mitochondrial functions at synapses with altered mitochondrial proteome and central metabolism in the mPFC. Pharmacological manipulation targeting mitochondria attenuated the synaptic shrinkage and depression-related behaviors. These findings show that chronic social stress alters the central metabolism at mPFC synapses, leading to neuronal pathology and depression-related behaviors.