Cytosolic phospholipase A2alpha (cPLA2) is a key mediator of tumorigenesis. In this study, by using a combination of pharmacological and genetic approaches in cell models and patient samples, we identify cPLA2 as a selective target to increase chemosensitivity in cervical cancer. We found that transcript and protein levels of cPLA2 but not other forms of cPLA2 (e.g., cPLA2 and cPLA2) were consistently increased in all tested malignant cervical cancer cells and tissues compared to normal counterparts, suggesting that cPLA2 upregulation is a common feature in cervical cancer. We further found that promoting growth and survival rather than invasion were the predominant roles of cPLA2 on cervical cancer. In addition, chemotherapeutic agents achieved similar to 100% inhibition efficacy in cPLA2-depleted cervical cancer cells, demonstrating the important role of cPLA2 in chemoresistance. Importantly, we identify that -catenin is critically involved in the molecular mechanism of cPLA2's action in cervical cancer. In summary, our work demonstrates the multiple essential roles of cPLA2 in cervical cancer, particularly in chemoresistance, via a -catenin-dependent manner. Our work also suggests that targeting cPLA2 has a therapeutic value in overcoming chemoresistance in cervical cancer or other cPLA2-regulated cancers.