OBJECTIVES: The aim of the present study was to determine the efficacy of green coffee bioactives in ameliorating the effects of high-fat diet (HFD)-induced obesity through in vitro and in vivo assessments. METHODS: Green coffee extract (GCE) was obtained by implementing a novel green extraction technique. The efficacy of GCE to inhibit in vitro pancreatic amylase and lipase was evaluated. Further, in vivo studies were conducted using a C57BL6 mice model grouped as starch-fed diet control, HFD control, HFD + positive control, HFD + GCE (100 mg/kg body weight), and HFD + GCE (200 mg/kg body weight). Animal body weight, diet intake, and fecal fat excretion were measured during the feeding period. On completion of the experiment, blood serum was collected for biochemical analysis, and organs were harvested for assessing the obesity-related biomarkers. RESULTS: The obtained GCE was enriched with polyphenols and alkaloids. GCE led to significant (P < 0.05) in vitro inhibition of pancreatic amylase and lipase. GCE supplementation considerably prevented weight gain in treated groups post-consumption of HFD. It also led to increased fecal fat excretion and regulated the high-fat-mediated blood glucose levels. GCE effectively modulated the blood lipid profile, morphology of adipose and liver tissues, and liver antioxidant defense enzymes and resulted in hepatoprotective effects. It also downregulated the genes associated with lipid biosynthesis. CONCLUSIONS: GCE exhibits promising results in suppressing the consequences associated with HFD-induced obesity. It has the potential to be incorporated into food products benefiting consumer health and food industries. CI - Copyright (c) 2023 Elsevier Inc. All rights reserved.