Social isolation (SI) is a prevalent issue in modern society, particularly exacerbated during the COVID-19 pandemic, and it is a significant contributor to depressive disorders. Inflammation-related markers are upregulated in patients with major depressive disorder (MDD) unresponsive to first-line selective serotonin reuptake inhibitor (SSRI) antidepressants. This study investigates the role of formyl peptide receptor 2 (FPR2), a G-protein coupled receptor expressed in central and peripheral immune cells, in SI-induced depression. We developed a mouse model of SI by housing mice individually for three weeks. SI mice exhibited increased capillary-associated microglia (CAMs) with upregulated FPR2 expression in the prefrontal cortex (PFC) and hippocampus compared to group-housed controls. Notably, subcutaneous administration of the FPR2 antagonist WRW4 alleviated depressive and anxiety-like behaviors in SI mice, reducing microglial activation and neuronal damage. WRW4 treatment decreased CAM numbers and their FPR2 expression. RNA sequencing revealed that SI primarily induced changes in genes associated with blood-brain barrier (BBB) function, followed by alterations in genes related to hormone activity, immune activation, and neuronal function. Transcriptomic changes in brain endothelial cells from SI mice resembled those observed in animal models of several neurological disorders and in MDD patients. WRW4 treatment partially reversed these transcriptomic alterations and restored compromised BBB integrity. Additionally, intracerebroventricular (ICV) injection of WRW4 also alleviated depressive and anxiety-like behaviors in SI mice. Finally, our analysis of public transcriptome databases indicates FPR2 upregulation in the orbital ventral PFC of MDD patients and peripheral blood mononuclear cells of those in severe depressive episodes. These findings suggest that the pharmacological targeting of FPR2 may rescue SI-induced pathology in mice by protecting BBB integrity.