Aim: To investigate the molecular mechanisms underlying triggering of apoptosis by hesperetin using in silico and in vitro methods. Methods: The mechanism of binding of hesperetin with NF-${kappa}B$ and other apoptotic proteins like BAX, BAD, $BCL_2$ and $BCL_{XL}$ was analysed in silico using Schrodinger suite 2009. In vitro studies were also carried out to evaluate the potency of hesperetin in inducing apoptosis using the human prostate cancer PC-3 cell line. Results: Hesperetin was found to exhibit high-affinity binding resulting from greater intermolecular forces between the ligand and its receptor NF-${kappa}B$ (-7.48 Glide score). In vitro analysis using MTT assay confirmed that hesperetin reduced cell proliferation ($IC_{50}$ values of 90 and $40{mu}M$ at 24 and 48h respectively) in PC-3 cells. Hesperetin also downregulated expression of the anti-apoptotic gene $BCL_{XL}$ at both mRNA and protein levels and increased the expression of pro-apoptotic genes like BAD at mRNA level and BAX at mRNA as well as protein levels. Conclusion: The results suggest that hesperetin can induce apoptosis by inhibiting NF-${kappa}B$.