Oxymatrine may inhibit tumor cell proliferation, induce cell cycle arrest, promote apoptosis, induce tumor cell differentiation and fight against tumor angiogenesis, as well as inhibit tumor invasion and metastasis. The present study aimed to investigate the anticancer effects of oxymatrine on nasopharyngeal cancer (NPC) cell death, and the underlying molecular mechanisms of these effects. NPC HK-1 cells were incubated overnight and treated with oxymatrine (0, 2, 4, 6 and 8 mg/ml) for 1, 2 or 3 days. The results demonstrated that oxymatrine significantly inhibited NPC cell proliferation in a time-and dose-dependent manner. Oxymatrine treatment also induced apoptosis, induced the activities of caspase-3 and caspase-9, promoted p53 and Bax protein expression, and suppressed cyclin D protein expression in these cells. The protein expression levels of phosphoinositide 3 kinase (PI3K), phosphorylated (p)-AKT, p-mammalian target of rapamycin, p-p70 ribosomal protein S6 kinase and nuclear factor (NF)-kappa B were significantly downregulated by oxymatrine treatment. In conclusion, results from the present study suggested that oxymatrine may induce NPC cell death through the inhibition of PI3K/AKT and NF-kappa B signaling pathways.