<p>Prostate cancer exhibits clinical challenges such as resistance to conventional chemotherapy drugs such as Cisplatin, especially in advanced stages, and the high cytotoxic effects of these drugs. This study investigated how Eriodictyol, a natural flavonoid, can enhance the anti-proliferative and apoptotic activity of Cisplatin in androgen-independent PC-3 prostate cancer cells by inhibiting the PI3K/Akt signaling pathway. Eriodictyol significantly inhibited PC-3 cell proliferation in a dose and time dependent manner and remarkable anti-proliferative activity was observed in its combination with Cisplatin at low dose (10&#xa0;µM) and time period (24&#xa0;h). The combination of drugs significantly suppressed the migration of PC-3 cells and caused remarkable morphological deteriorations consistent with the apoptotic process. Eriodictyol did not show a cytotoxic effect against HUVEC cells. Combined administration induced a high level of enhanced pro-apoptotic response through upregulation of Caspase-3, -8, -9 and pro-apoptotic proteins (p53, Bax, Bik) compared to single administrations. Conversely, anti-apoptotic proteins (Bcl-2, Survivin) were downregulated. Furthermore, phosphorylated PI3K and Akt levels were significantly decreased in the combination group, which was consistent with the apoptotic response by inhibition of PI3K/Akt pathway. In conclusion, Eriodictyol enhanced the apoptotic response in PC-3 cells with minimal drug exposure at low dose and duration, reduced migration, and increased the anti-cancer efficacy of Cisplatin by inhibiting the PI3K/Akt pathway. These results indicated that it is promising as a safe and effective adjuvant in the treatment of prostate cancer. We need further and detailed in vivo studies to potentially validate our findings clinically.</p>