Chronic diseases such as obesity and type II diabetes lead to the development of non-alcoholic fatty liver disease (NAFLD). Coffee by-products, including coffee husk and silverskin, are considered a source of bioactive compounds. Owning to their proven ability to regulate cellular metabolic processes, phytochemicals from coffee by-products could modulate liver metabolism preventing NAFLD. Hence, this study aimed to assess the effect of the primary phytochemicals from coffee by-products and two aqueous extracts from coffee husk and silverskin on the regulation of lipid and glucose metabolism in hepatocytes using and in vitro model of NAFLD. Coffee husk and silverskin were used to prepare two aqueous extracts (CHE and CSE, respectively) using water. The phytochemical composition was determined using UPLC-MS/MS analysis. An in vitro model of NAFLD was used: HepG2 cells were co-treated with 10-50 µmol L^-1 of either pure caffeine, chlorogenic acid, caffeic acid, protocatechuic acid, gallic acid, and kaempferol, CHE, or CSE (20-100 µg mL^-1) in the presence or absence of palmitic acid (PA, 500 µmol L^-1). Different biomarkers of cell metabolism were assessed 24 h after the co-treatment in cell supernatants and lysates using chemical, biochemical, and immunochemical techniques. Phytochemicals from coffee by-products decreased PA-triggered lipid accumulation (16-94%, p < 0.05) by reducing fatty acid synthase activity and stimulating lipolysis (8-83%, p <0.05). CHE, CSE, and therein-bioactive compounds promoted glucose uptake (13-45%) via the increase in the phosphorylation of the insulin receptor (1.9 to 2.7-fold), protein kinase B (AKT) (1.4 to 3.1‐fold), AMPKα (1.6 to 2.4-fold), and PTEN (2.0 to 4.2-fold). In conclusion, our results proved that phytochemicals from coffee by-products, mainly caffeine and chlorogenic acid, could regulate hepatic lipid and glucose metabolism. Overall, our results generate new insights into the use of coffee by-products as a sustainable food ingredient to encounter NAFLD.