Human ovarian cancer is a highly aggressive malignancy in women, characterized by high mortality and poor prognosis. Dysregulation of microRNAs (miRNAs) plays a critical role in the pathogenesis of various cancers, including ovarian cancer. Among these, miR-34a functions as a tumor suppressor miRNA and represents a promising target for cancer therapy. Downregulation of miR-34a in ovarian cancer has been associated with disease initiation and progression. Sericin, a silk-derived glycoprotein, possesses diverse biological activities, including antioxidant, anti-inflammatory, and anticancer properties. The present study, for the first time, investigated the potential effects of sericin on miR-34a-mediated apoptotic pathways in the human ovarian cancer cell line OVCAR3. OVCAR3 cells were treated with sericin at concentrations of 2 mg/mL and 64 mg/mL for 48 h. The expression level of miR-34a was quantified using real-time quantitative PCR (qPCR), while the protein expression levels of the anti-apoptotic protein B-cell lymphoma 2 (Bcl-2) and the pro-apoptotic protein Bcl-2-associated X protein (BAX) were evaluated by Western blot analysis. Sericin treatment at both 2 mg/mL and 64 mg/mL significantly upregulated miR-34a expression and increased BAX protein levels in OVCAR3 cells. Moreover, sericin at 64 mg/mL markedly decreased Bcl-2 protein expression. Given the central role of Bcl-2 in conferring resistance to anticancer therapies and the importance of apoptosis dysregulation in tumor progression and therapeutic resistance, these findings suggest sericin as a promising anticancer agent. In summary, the results indicate that sericin exerts its anticancer effect, at least in part, through activation of a miR-34a-dependent apoptotic pathway.