Ovarian cancer (OC) is the 3rd most common type of the gynecological malignancy. Although current treatment strategies have greatly improved, there is still a need to develop new biomarkers for OC diagnosis and treatment. Microtubule affinity regulated kinase 2 (MARK2) is a kinase involved in the progression of multiple tumors. However, whether abnormal expression of MARK2 is associated with OC progression needs further analysis. We here revealed its role in OC. We found high expression of MARK2 in OC. Knockdown of MARK2 inhibited proliferation of OC cells, stimulated apoptosis of OC cells, and restrained glucose metabolism of OC cells. Furthermore, MARK2 regulated phosphatidylinositol 3-kinase/PKB (protein kinase B)/tumor suppressor protein 53 (PI3K/AKT/p53) axis in OC, therefore affecting the progression of OC. In summary, MARK2 knockdown suppressed cell proliferation by regulating PI3K/AKT/p53 axis.