Background The liver cancer is one of the most frequent solid organ malignancies worldwide. Alternative medicine is deemed as one approach that may progress anticancer drugs efficacy and minimize their toxic effects. Similarly, this study was designed to establish the ethanolic extract from Artemisia judaica (AJ) plant and characterize extract that formed using gas chromatography–mass spectrometry analysis, then evaluate their anti-tumour activity alone or in combination with cyclophosphamide(CTX) against trichloroacetic acid (TCA)-induced hepatocellular carcinoma in rats. Results The obtained results revealed that a significant elevation in serum transaminases (ALT, AST), and alkaline phosphatase activities, as well as total serum bilirubin (T.Bil) levels, was recognized in TCA injected rats compared with the control group. In contrast, a significant decrease in liver antioxidant enzymes superoxide dismutase and catalase activities, as well as reduced glutathione level was observed in TCA treated rats compared with the control group. Furthermore, administration of AJ alone or in combination with CTX in rats presented a significant amelioration in all mentioned parameters and attenuated the increased malondialdehyde level in liver tissues compared to the TCA group. Conclusions It could be suggested that AJ hepatoprotective effect against chemical-induced hepatocarcinogenesis in combination with chemotherapy drug by reducing chemotherapy side effects confirmed by haematoxylin and eosin stain (H&E) observations, improvement of oxidative stress biomarkers, and liver enzymes.