Objective To observe the inhibitory effect of oxymatrine (OMT) combined with all-trans retinoic acid(ATRA) on diethylnitrosamine (DEN)-induced hepatocellular carcinoma in rats, and to explore its mechanism of action.Methods A rat model of hepatocellular carcinoma was established by DEN induction for 18 weeks. Wistar rats wererandomly divided into control, model, and intervention groups. Rats were killed at 6, 12, and 18 weeks after cancerinduction. Pathological changes of the liver tissues were observed by hematoxylin and eosin (HE) staining, related indexesof rat liver function were detected, and interleukin (IL)-6 expression was detected by enzyme-linked immunosorbent assay.The mRNA expressions of let-7a, nuclear factor (NF)-κB-p65, IL-6, and signal transducer and activator of transcription(STAT)3 were detected by quantitative real-time (RT-q)PCR, while the changes of STAT3 and p-STAT3 proteins weredetected by western blotting. Results The pathological examination revealed a significantly decreased number of livercancer nodules in the intervention group compared with the model group ( P <0. 05), while levels of serum IL-6, alanineaminotransferase(ALT), glutamyl transpeptidase(GGT), aspartate aminotransferase(AST), and alkaline phosphatase(ALP) were significantly lower ( P < 0. 05). RT-qPCR results showed that the expression of let-7a was significantlyincreased in the intervention group compared with the model group, while that of NF-κB-p65, IL-6, and STAT3 wassignificantly decreased ( P <0. 05). At the 18th week of the experiment, the expressions of STAT3 and p-STAT3 in theintervention group were significantly lower than in the model group ( P <0. 05). Conclusions OMT combined with ATRA can significantly inhibit DEN-induced hepatocarcinogenesis in rats and delay the growth of tumors to some extent.