Major depressive disorder (MDD) is a leading cause of disability worldwide, but its pathogenesis is unclear. Mounting evidence implicates the loss of blood-brain barrier (BBB) integrity as it exposes the brain to harmful inflammatory mediators, antibodies, and serum proteins, but to date no pharmacotherapies specifically target the BBB. Focused ultrasound (FUS) is a non-invasive, neuromodulatory strategy that transiently opens the BBB (FUS-BBBO) when coupled with microbubbles. Here, we examine FUS-BBBO as an independent therapy in a mouse model of stress-induced depression. Briefly, adult male and female mice were administered a 3-shock contextual fear conditioning (CFC) paradigm. Twenty-four hours later, mice were given a sham or FUS-BBBO procedure targeted to the hippocampus. T1-weighted MRI validated targeting. Four days later, mice were re-exposed to the CFC context to assay freezing behavior. Depressive-like, anxiety-like, locomotor, perseverative, and hyponeophagia were measured on subsequent days. Brain tissue was immunostained for Claudin-5 (CLDN5), the most highly expressed tight junction protein in the BBB. We report that a single administration of FUS-BBBO reduces behavioral despair in male, but not female, mice. Staining results show that CLDN5 is significantly decreased following CFC, and this effect is rescued by FUS-BBBO administration. In addition, baseline CLDN5 expression is less in female mice when compared to male mice. These data indicate that FUS-BBBO can act as a novel antidepressant through CLDN5 remodeling.