Ubiquitin-specific peptidase (USP)18 is elevated in tumor tissues and is associated with tumor malignancy. USP18 functions as an oncogene in different cancers. However, the role of USP18 in ovarian cancer was poorly understood. TCGA database showed that USP18 was elevated in ovarian cancer tissues. Additionally, USP18 mRNA and protein expression was also up-regulated in tumor tissues. The functional assays were then designed via siRNA-mediated knockdown of USP18. The results showed that knockdown of USP18 reduced cell viability and ovarian cancer proliferation. Furthermore, cell apoptosis was promoted by USP18 silencing, and interference of USP18 suppressed cell migration and invasion. The expression of phosphorylated AKT (p-AKT) and p-mTOR protein was decreased in ovarian cancer cells by USP18 knockdown. Inhibition of AKT attenuated the decrease in cell apoptosis induced by USP18 overexpression and increased cell viability and migration. In conclusion, USP18 promoted the proliferation and migration of ovarian cancer cells by activating AKT/mTOR signaling.