Trifolium resupinatum L., Fabaceae, aqueous methanol leaf extract was selected to mitigate some obesity-associated risk factors to validate the possibility of further developing herbal drugs. Chromatography and spectrophotometric techniques verified 14 phenolics, five of which were first isolated from the plant and identified as 6''-O-acetyl ononin, genistin, daidzin, sissotrin, and astragalin. Further phytochemical characterization was performed via liquid chromatography-electrospray ionization-mass spectrometry assisted by a spectral similarity molecular network. In total, 81 metabolites were tentatively annotated including 69 species-first dereplications. Two major isolates (formononetin and pseudobaptigenin) were selected along with the investigated extract for an in vitro pancreatic lipase inhibition assay. They showed notable effects with IC50 values (µg/ml): 47.2 ± 1.1, 112.8 ± 1.23, and 471.32 ± 0.8, respectively, incomparable to orlistat (23.8 ± 0.64). Preliminary in vivo assay (25 mg/kg extract, daily, 8 weeks) displayed weight loss interest and promising advancement of serum triacylglycerides, total cholesterol, and glucose levels. Molecular docking studies confirmed the promising binding score of formononetin and pseudobaptigenin near the active sites and highlighted the affinity of other isolates to the lipase enzyme. Several isolates passed Lipinski’s law of the drug-likeness test, whereas SwissADME radar displayed that all constituents fall within the acceptable bioavailability zone. Therefore, the combination of flavonoids, especially isoflavones, could be regarded as drug-like agents for protection against obesity-induced metabolic complaints.Graphical