The present study investigates the efficacy of Terminalia muelleri ethanol extract (TME) in alleviating the oxidative stress and inflammation that could be the main player of hepatocellular carcinoma (HCC) development and progression. Forty-eight male albino rats were divided into two main groups (32 rats for DENA administration; 16 rats for control groups); after the induction period of DENA administration (6 weeks), the HCC-induced rats were treated with TME, DOX, or their combination for eight weeks. The obtained results revealed that the DENA induced HCC resulted in remarkable dysregulation in the circulatory levels of TNF-α and IL-10 that accompanied by the initiation of free radicals with the generation of the oxidative stress, in addition to an increase in the mRNA expression levels of NFkB, MMP 9 and downregulation of mRNA expression level of TIMP1. The treatment of HCC induced rats with DOX, TME, or their combination alleviated and suppressed the progression of HCC in the following manner TME + DOX followed by TME then DOX. The obtained results revealed that TME was more valuable as an anti-cancer agent than DOX, employed in the current study as reference chemotherapy. T. muelleri extract attenuates inflammation, oxidative stress, and extracellular matrix proteolysis in hepatocellular carcinoma-induced rats.