Abstract: Background and Objective: Non-alcoholic fatty liver disease (NAFLD) is not only the most common cause of liver diseases in humans but also it may complicate and become a risk factor for liver cancer. The present work aimed to evaluate the anticancer activity (in vitro) of quinoa and safflower seeds powder and their beneficial effects against NAFLD (in vivo). Materials and Methods: Proximate analysis, fatty acids profile, total phenolic and phytic acid of quinoa and safflower seeds were assessed. Also their anticancer activities (in vitro) against liver cancer were evaluated. The preventive effect of both seeds on NAFLD was evaluated using twenty four male rats. NAFLD was induced in rats by high fructose diet (HFD) for 4 weeks. The effects of HFD and HFD supplemented with 20% quinoa or safflower powder on plasma and liver lipids, lipid peroxidation, total protein, albumin as well as liver and kidney functions were determined. Results: Quinoa seeds powder was promising in cytotoxicity against hepatocarcinoma cell line HEPG2 (IC50 was 14.6 μg). Feeding rats on HFD produced dyslipidemia and significant increase in liver functions and lipid peroxidation with significant elevation in liver triglycerides and total cholesterol. Quinoa and safflower seeds powder produced improvement in the biochemical parameters with different degrees. Conclusion: Quinoa and safflower seeds powder possessed cytotoxicity against hepatocarcinoma cell line HEPG2 and afford hepato-protection against NAFLD.