Aripiprazole (ARI), a second-generation atypical antipsychotic drug approved for schizophrenia treatment, shows good efficacy against depression. However, the poorly aqueous solubility of ARI leads to low bioavailability and increased dose-related side effects, seriously limiting its application in pharmaceutics. Herein, we demonstrated the fabrication of ARI and poly (methyl vinyl ether-co-maleic anhydride) (PVMMA) composite nanoparticles (PA NPs) using the supercritical antisolvent (SAS) process for enhancing its water-solubility and curative anti-depressant effects. Initially, the optimal experimental conditions (ARI/PVMMA mass ratio of 1:6, pressure of 10 MPa, and solution flow rate of 0.75 ml min-1) were determined by a 23 factorial experimental design, resulting in the PA NPs with an excellent particle morphology. In vitro cell experiments showed that PA NPs significantly inhibited the inflammatory response caused by the microglia activation induced by lipopolysaccharide (LPS). Similarly, mice behavioral tests demonstrated that PA NPs significantly improved LPS-induced depression-like behavior. Importantly, compared with free ARI, the LPS-induced activation of microglia in the mouse brain and the expression of inflammatory factors in serum were significantly reduced after treatment with PA NPs. Together, the innovative PA NPs designed by SAS process might provide a candidate for developing new ARI-based nano-formulations.