The involvement of hypoxia-inducible factor-1 alpha (HIF-1 alpha), transforming growth factor-beta 1 (TGF-beta 1), Smad and beta-catenin signaling pathway in non-alcoholic fatty liver disease (NAFLD) is not fully elucidated. Pioglitazone improves NAFLD, whereas the underlying molecular mechanisms are not extensively clarified. In addition, cranberry and cinnamon have received increasing attention as potential therapeutic agents in metabolic disorders. Hence, this study aimed to test the hypothesis that the downregulation of HIF-1 alpha/TGF-beta 1/Smad/beta-catenin signaling might underlie the pioglitazone effect in HFD-induced liver steatosis in rats. In addition, the study aimed to determine whether the concurrent use of cranberry and/or cinnamaldehyde would boost biochemical and molecular gains of pioglitazone while limiting its significant side effect; weight gain. Rats were kept on a high-fat diet for 14 weeks, and HFD rats were orally treated with pioglitazone, cranberry, or their combinations for 8 weeks. Pioglitazone, cranberry, and to a lesser extent cinnamaldehyde significantly ameliorated the pathological lesions, improved the hepatic histological structure of cinnamaldehyde, and successfully rectified liver index, AST, ALT, lipid profile, hepatic triglycerides, and HOMA-IR. They also inhibited HIF-1 alpha, beta-catenin, TGF-beta 1 and subsequently inhibited phosphorylated/total Smad2/3 and their ratios. In conclusion, the beneficial effects of this combination in HFD-induced hepatic steatosis might be attributed to the modulation of hypoxia/HIF-1 alpha, TGF-beta 1/Smads, and Wnt/beta-catenin pathways in the liver. Thus, cranberry and cinnamon might be potential add-on agents to other pharmacotherapies in liver steatosis.