Crassocephalum rubens falls under the wild edible, under-cultivated traditional leafy vegetables (TLV) in Africa; it is used by locals in managing diabetes mellitus among other diseases. This study investigated the in vitro, ex vivo antioxidant and antidiabetic potentials of different extracts of C. rubens. The ameliorative effects of the extracts on Fe -induced oxidative injury was investigated ex vivo together with the effects of the aqueous extract on intestinal glucose absorption and muscle glucose uptake in freshly harvested tissues from normal rats. The aqueous extract was subjected to Liquid Chromatography-Mass Spectrometry (LC-MS) analysis to identify possible bioactive compounds which were then docked with the tested enzymes through in silico modeling. The extracts exhibited antioxidant activity, inhibited α-glucosidase and lipase enzyme activities, intestinal glucose absorption and enhanced muscle glucose uptake compared to controls. Sanguisorbic acid dilactone identified through LC-MS analysis showed a high binding affinity for catalase and lipase enzymes. PRACTICAL APPLICATIONS: The results of this study suggest that the aqueous extract of C. rubens possesses better antioxidant and possible antidiabetic potentials compared to other extracts which could be associated to the synergistic action of its identified bioactive compounds.