Hepatocellular carcinoma (HCC) is deadly and intricate cancer primarily linked to oxidative stress and inflammation in the hepatic tissue. This study attempted to look into methotrexate (MTX) impact against HCC. Three groups of rats were categorized. Group I (a normal control group). Group II (Diethylnitroseamine (DENA)/Carbon tetrachloride (CCL4) group): HCC group; 200 mg of DENA per kg b.w. i.p. was administered to rats once. 3 ml of CCl4 per kg b.w. s.c. per week for six weeks, following two weeks of DENA application to enhance the carcinogenic impact. Group III (treated): methotrexate (MTX) treated; rats were given MTX at dose of 0.1 μM/week/ i.p. for 4 weeks after receiving injections of DENA/CCL4 at doses comparable to those in group 2. DENA/CCL4 injection resulted in substantial increase in serum AST, ALT, ALP activities, hepatic inflammatory markers (IL-6, TNF-α), and hepatic MDA levels, in addition to non-significant decrease in hepatic TAC level. Treatment with methotrexate to HCC rats caused marked improvement effects in all biochemical parameters. According to these findings, methotrexate might be considered as an effective option in hepatic cancer treatment.