Approximately 90% of the coffee cherry is discarded as waste during coffee bean processing. Coffee pulp has been validated as a safe potential ingredient and is a potential source of nutrients and health-promoting compounds that could be used as nutraceuticals to manage some chronic diseases. Metabolic disorders associated with dysregulated energy and cellular processes, such as obesity and hyperlipidemia, contribute to non-alcoholic fatty liver disease (NAFLD). In this sense, the main objective of this study was to evaluate the impact of an in vitro simulated digestion on the hypolipidemic properties of coffee pulp flour and the biological activity of the digested fractions of its flour and extract in HepG2 cells. The hypolipidemic properties of coffee pulp flour were tested by measuring the capacities of the residual fraction of each digestion to bind cholesterol and bile salts and to inhibit the lipase activity after simulated gastric, intestinal, and colonic in vitro digestion. The results exhibited that coffee pulp residual fraction had up to a 58% (p < 0.05) more capacity to bind cholesterol, 1.9-fold (p < 0.05) higher bile salts binding capacity, and 1.5-fold (p < 0.05) higher ability to reduce the lipase activity than control residues. Likewise, the digested fractions of coffee pulp flour and extract (50-250 µg/mL) significantly (p < 0.05) alleviated the accumulation of fat (14-35%), triglycerides (5-27%), and cholesterol (9-48%) triggered by the stimulation of HepG2 cells with palmitic acid (500 µM) to simulate NAFLD. In conclusion, simulated gastrointestinal and colonic digestion improves coffee pulp hypolipidemic properties, enhancing its biological activity in cell culture models. Therefore, this coffee by-product could be an interesting potential ingredient to be used to prevent hyperlipidemia and regulate lipid metabolism.