The utilization of food industry by-products for health-promoting purposes is gaining attention, with a cocoa shell extract (CSE) emerging as a promising candidate. Rich in bioactive compounds such as methylxanthines, (poly)phenols, and dietary fiber, the cocoa shell demonstrates antioxidant, anti-inflammatory, lipid-lowering, and vasoactive properties. Hence, our objective was to investigate the impact of CSE intake on the rat plasma metabolome. By employing untargeted metabolomics and a chemometric analysis, we aimed to identify the key metabolites and enriched metabolic pathways influenced by the cocoa shell, thereby elucidating the plasmatic changes induced by this dietary intervention. Female rats were supplemented with a daily dose of 250 mg/kg CSE over seven days. Plasma samples were collected at baseline, day 4, and day 7, and subjected to untargeted metabolomic profiling using LC-ESI-QTOF. The analysis identified 244 metabolites, revealing significant reconfigurations by day 7. Enhanced pathways included caffeine, glycerophospholipid, nicotinate, and nicotinamide metabolism, indicating increased lipid metabolism and energy homeostasis. Conversely, reductions in tryptophan, glutathione, arginine, and proline pathways suggested alterations in amino acid metabolism and antioxidant defenses. A network analysis further highlighted significant changes in the cholinergic synapse, retrograde endocannabinoid, and glutamatergic synapse pathways, crucial for cellular communication and neurotransmission. These findings underscore the rapid modulation of the metabolome by CSE intake, demonstrating the bioavailability of key components like methylxanthines. This study's results suggest that CSE, a sustainable cocoa by-product, could serve as a functional food ingredient, promoting metabolic health through its effects on lipid metabolism, energy homeostasis, and neurotransmission pathways. This research not only advances our understanding of the biological activity of CSE but also supports its potential application in dietary interventions aimed at enhancing metabolic and cardiovascular health, thus contributing to the sustainable use of food by-products and their potential in health promotion.