MicroRNAs have been implicated in atherosclerosis (AS) progression. Here, we focused on how miR-320a affect AS progression via vascular smooth muscle cells (VSMCs). Oxidized low-density lipoproteins (ox-LDL)-stimulated VSMCs were used as an AS cell model, and qRT-PCR was performed to measure miR-320a and regulators of G protein signaling (RGS5) levels. CCK-8 and wound healing assays were used to detect the viability and migration of VSMCs. Western blotting was used to measure the protein expression levels of PCNA, Bax, and Bcl-2. The interaction of miR-320a and RGS5 was determined by dual luciferase and RNA pull-down assays. MiR-320a was highly expressed, whereas RGS5 showed low levels of expression in the arterial plaque tissues. Silencing of miR-320a blocked cell viability and migration, inhibited expression of the proliferation-specific protein PCNA in ox-LDL-treated VSMCs, promoted Bax protein expression, and inhibited Bcl-2 protein expression. Furthermore, miR-320a was found to exert these effects by inhibiting RGS5 expression. Collectively, miR-320a promoted cell viability, migration, and proliferation while reducing apoptosis of ox-LDL-stimulated VSMCs by inhibiting RGS5.