The energetic costs of behavioral chronic stress are unlikely to be sustainable without neuronal plasticity. Mitochondria have the capacityto handle synaptic activity up to a limit before energetic depletion occurs. Protective mechanisms driven by the induction of neuronalgenes likely evolved to buffer the consequences of chronic stress on excitatory neurons in prefrontal cortex (PFC), as this circuitry isvulnerable to excitotoxic insults. Little is known about the genes involved in mitochondrial adaptation to the buildup of chronic stress.Using combinations of genetic manipulations and stress for analyzing structural, transcriptional, mitochondrial, and behavioral outcomes,we characterized NR4A1 as a stress-inducible modifier of mitochondrial energetic competence and dendritic spine number inPFC. NR4A1 acted as a transcription factor for changing the expression of target genes previously involved in mitochondrial uncoupling,AMP-activated protein kinase activation, and synaptic growth. Maintenance of NR4A1 activity by chronic stress played a critical role inthe regressive synaptic organization in PFC of mouse models of stress (male only). Knockdown, dominant-negative approach, andknockout of Nr4a1 in mice and rats (male only) protected pyramidal neurons against the adverse effects of chronic stress. In human PFCtissues of men and women, high levels of the transcriptionally active NR4A1 correlated with measures of synaptic loss and cognitiveimpairment. In the context of chronic stress, prolonged expression and activity of NR4A1 may lead to responses of mitochondria andsynaptic connectivity that do not match environmental demand, resulting in circuit malfunction between PFC and other brain regions,constituting a pathological feature across disorders.