Metabolic syndrome (MS) is a cluster of risk factors for the development of cardiovascular disease and type 2 diabetes mellitus. Some dietary bioactive compounds such as peptides can exert dual antioxidant and anti-inflammatory effects. The aim of this study was to analyze the effects of microencapsulated brewers' spent grain peptides (BSG-P-MC) on hepatic injury, lipid peroxidation, oxidative stress and inflammation in the liver-spleen axis in Wistar rats fed with a sucrose-rich diet (SRD). Male rats received for 100 days a reference diet (RD), SRD or RD and SRD containing 700 mg per kg body weight per day of BSG-P-MC. The results demonstrated that BSG-P-MC reversed injury, lipid peroxidation, and oxidative stress in the liver. For the spleen, BSG-P-MC decreased the levels of lipid peroxidation, CAT activity, NFκB, PAI-1 and F4/80 protein mass levels with respect to the SRD-fed rats. Three peptides identified by LC-MS/MS from BSG-P-MC after in vitro gastrointestinal digestion showed high in silico free radical scavenging activity (LPRDPYVDPMAPLPR, ANLPRDPYVDPMAPLPRSGPE and ANLPRDPYVDPMAPLPR). Moreover, two identified peptides presented high in silico anti-inflammatory properties (LTIGDTVPNLELDSTHGKIR and VDPDEKDAQGQLPSRT). This study is the first report of antioxidant and anti-inflammatory properties of microencapsulated BSG-peptides exerted in the liver-spleen axis in a MS rodent model.