Our previous reports have shown that microRNA‐4651 is a potential early diagnostic and prognostic marker for hepatocellular carcinoma. We aimed to investigate whether microRNA‐4651 modified postoperative adjuvant transarterial chemoembolization (pa‐TACE) to improve the prognosis of hepatocellular carcinoma. A hospital‐based retrospective study, including 302 patients with advanced‐stage hepatocellular carcinoma who received tumor resection or tumor resection plus pa‐TACE as an initial therapy, was conducted to assess the effects of microRNA‐4651 on pa‐TACE treatment. MicroRNA‐4651 expression in tumor tissues was tested using the TaqMan‐PCR technique. The sensitivity of tumor cells to doxorubicin (an anticancer drug used in pa‐TACE procedure) was analyzed by the half‐maximal inhibitory concentration (IC50). Upregulated microRNA‐4651 expression in tumor tissues can improve the therapeutic response of patients with hepatocellular carcinoma on pa‐TACE (hazard ratios [95% confidence intervals] = 0.32 [0.22‐0.46] for death risk and 0.39 [0.28‐0.56] for tumor‐recurrence risk, respectively), but downregulated expression cannot. Functional analyses–displayed microRNA‐4651 mimics decreased while its inhibitor increased the IC50 of tumor cells to doxorubicin (0.65 [0.61‐0.69] versus 2.17 [1.98‐2.37] µM). Cytochrome P450 2W1 was shown as a possible target of microRNA‐4651. Additionally, dysregulation of microRNA‐4651 also affected the clinical pathological features of hepatocellular carcinoma and was an independent prognostic factor for this cancer. Conclusion: These results indicate that increasing microRNA‐4651 expression may be beneficial for pa‐TACE in improving hepatocellular carcinoma prognosis.