Hepatocellular carcinoma (HCC) is one of the most common digestive system malignant tumors. Due to the resistance to radiotherapy, the prognosis in patients with HCC is poor. Based on previous studies and online tools prediction, we hypothesized that miR-92b, which was reported to promote HCC cell proliferation, might bind to p57kip2, a well-known tumor suppressor, to modulate the radioresistance of HCC to ionizing radiation (IR) -based radiotherapy. In the present study, a higher miR-92b expression in HCC tissues and cell lines was observed; a high miR-92b expression was correlated with poorer prognosis in patients with HCC. The overexpression of miR-92b enhanced the radioresistance of HCC to IR treatment by promoting cancer cell proliferation, attenuating cell apoptosis and remove IR-induced cell cycle at G2/M phase. Through directly binding to the 3'-UTR of p57kip2, miR-92b negatively regulated the protein levels of p57kip2; miR-92b inhibition enhanced the cell effect of IR on HCC cells, which could be attenuated by the p57kip2 knockdown, in other words, miR-92b modulated the radioresistance of HCC to IR-based radiotherapy through p57kip2. Taken together, miR-92b inhibits p57kip2 expression in HCC tissues and cell lines, thus enhancing the radioresistance of HCC to IR-based radiotherapy; targeting miR-92b to rescue p57kip2 expression in HCC might help sensitive HCC cells to IR-based radiotherapy.