Background: Chronic stress exposure is a risk factor for several psychiatric disorders, including post-traumatic stress disorder (PTSD) and major depression (MDD), with the prefrontal cortex (PFC) playing a key role in mediating this stress susceptibility. However, most individuals who are exposed to chronic stress are resilient and do not develop psychopathology. Recent evidence suggests that glial cells, especially astrocytes, play an important role in controlling stress-induced anxiety- and depression-like behavior, yet their role in contributing to stress resilience is not understood. Methods: Using fiber photometry, chemogenetics, and RNA-sequencing in male mice, we establish a role for PFC astrocytes in stress resilience. Results: We demonstrate that stress-induced increases in astrocytic calcium activity are both necessary and sufficient for resilience. Bioinformatic analysis reveals robust transcriptional responses in PFC astrocytes that differ between susceptible vs. resilient mice and are unique when compared to astrocytic transcriptional changes in other limbic regions. Comparison with human RNA-sequencing data indicates that molecular changes observed in PFC astrocytes from susceptible mice converge with gene expression changes observed in MDD patients. Conclusions: Together, these data support targeting astrocytes as a potential therapy for negative behavioral consequences following stress exposure and reveal potential molecular mechanisms within PFC astrocytes that could contribute to depressive-like behaviors.