A disequilibrium between energy intake and expenditure is the principal cause of obesity. This metabolic disorder is defined as an excessive accumulation of adipose tissue and is closely associated with the increasing prevalence of non-alcoholic fatty liver disease (NAFLD). Modifying the diet to prevent obesity and its comorbidities is the primary treatment for NAFLD. In this context, finding novel ingredients that may help us to reduce the incidence of these disorders is necessary. Cocoa shell is a cocoa by-product verified as a safe ingredient and a potential source of nutrients and health-promoting compounds. Hence, the main objective of this study was to evaluate, after an in vitro simulated digestion, the hypolipidemic properties of the residual fraction of cocoa shell flour and biological activity of the digested fractions of cocoa shell flour and extract in HepG2 cells. An in vitro static digestion (INFOGEST) of cocoa shell flour was used to establish the capacity of the residual fraction to bind cholesterol and bile salts and to inhibit lipase. The results showed that the residual fraction of cocoa shell had up to 65.2% more capacity to bind cholesterol, 90.5% more capacity to bind bile salts. Moreover, digestion improved (1.6-fold, p < 0.05) the ability to reduce the lipase activity of the residual fraction of cocoa shell. NAFLD was induced in HepG2 cells by the treatment with palmitic acid (PA, 500 µM). The digested fractions of the flour and extract from cocoa shell (50-250 µg/mL) significantly (p < 0.05) reduced the accumulation of fat (17-42%), triglycerides (9-38%), and cholesterol (11-54%) in PA-treated HepG2 cells. In conclusion, digestion positively impacted the hypolipidemic properties of cocoa shell leading to enhanced biological activity in vitro and in cell culture models. Since cocoa shell might be used as a safe novel ingredient to prevent hyperlipidemia and regulate lipid metabolism, future animal and clinical investigations will be necessary to confirm the effects observed in vitro.