Background <p>Ovarian cancer (OC) is one of the most lethal gynecological malignant tumors globally.</p> Objectives <p>The objective of this research was to investigate the clinical significance and biological roles of the microRNA (miR)-758-5p/MMP-2 axis in OC.</p> Materials and methods <p>This study recruited 150 epithelial ovarian cancer (EOC) patients. The Kaplan-Meier survival analysis examined the association between miR-758-5p levels and patient survival outcomes. Cox regression analysis identified critical factors influencing patient mortality risk. RT-qPCR quantified the expression of miR-758-5p and matrix metalloproteinase-2 (MMP-2). Cell proliferation was assessed by the CCK-8 assay, while cell migration and invasion were evaluated by the Transwell assay. Flow cytometry was utilized to measure the cell’s apoptosis rate. The dual-luciferase reporter assay confirmed the targeted regulatory relationship.</p> Results <p>MiR-758-5p was reduced in EOC patients (<i>P</i> &lt; 0.0001). The expression of miR-758-5p (HR = 0.272, 95%CI = 0.131–0.561, <i>P</i> &lt; 0.001), lymph node metastasis (HR = 1.951, 95%CI = 1.085–3.506, <i>P</i> = 0.026), and tumor stage (HR = 2.125, 95%CI = 1.108–4.078, <i>P</i> = 0.023) were critical factors influencing patient mortality risk. Specifically, high expression of miR-758-5p was significantly correlated with improved patient survival outcomes. Moreover, elevated levels of miR-758-5p effectively suppress the proliferation, migration, and invasion of OC cells while promoting apoptosis (<i>P</i> &lt; 0.0001). The study further revealed that miR-758-5p directly negatively regulated MMP-2 expression. Overexpression of MMP-2 partially counteracted the effects of the miR-758-5p mimic on cell behavior (<i>P</i> &lt; 0.0001).</p> Conclusion <p>The miR-758-5p/MMP-2 axis may play a critical role in the OC progression.</p>