Members of the genus Euphorbia have attracted much interest as potential sources of bioactive compounds. In this study, the ethyl acetate, methanolic and aqueous extracts of aerial parts of three Euphorbia species namely Euphorbia hirta L., Euphorbia heterophylla L. and Euphorbia convolvuloides Hochst. ex Benth. were screened for their antioxidant [2,2-diphenyl-1-picrylhydrazyl (DPPH), 2,2′-azino-bis (3-ethylbenzothiazoline-6-sulfonic acid) (ABTS), ferric reducing antioxidant power (FRAP), cupric antioxidant reducing capacity (CUPRAC), metal chelating, total antioxidant capacity (phosphomolybdenum)], and enzymatic properties [α-amylase, α-glucosidase, tyrosinase, acetyl- (AChE), butyryl-cholinesterase (BChE)]. Total phenolic (TPC), total flavonoid content (TFC) and phytochemical profile were established via LC-DAD-MSn. Results showed that the methanolic and aqueous extracts of the three plants yielded the highest TPC with values ranging from 35.84–141.90 mg gallic acid equivalent/g. E. hirta was the most potent DPPH scavenger and chelator reporting the highest equivalent [DPPH: 195.22 mg Trolox equivalent (TE)/g, chelator: 30.73 mg ethylenediaminetetraacetic acid equivalent (EDTAE)/g], while E. heterophylla demonstrated the most significant Fe3+ and Cu2+ reducing potential (FRAP: 194.28 mg TE/g; CUPRAC: 631.25 mg TE/g) and possessed the highest total antioxidant capacity (3.76 mmol TE/g). The AChE, BChE, α-amylase and α-glucosidase enzyme inhibitory effects of the three species were relatively the same. However, E. hirta exhibited the highest anti-tyrosinase activity (109.71 mg kojic acid equivalent /g). Euphorbia convolvuloides showed low antioxidant activities and enzymatic inhibitory effects compared to other. LC-DAD-MSn fingerprint of the phenolics of the three species showed the presence of different derivatives. Quantitative data revealed tannins and flavonoids (25 and 20 mg/g respectively) for E. hirta, high amount of tannins 63 and 21 mg/g of flavonoids for E. heterophylla, while high flavonoid contents for E. convolvuloides, 56 mg/g. Euphorbia hirta proved to the most promising among the three tested species and thus can be explored further by isolating and characterizing active bioactive agents that could be used to manage oxidative stress-related diseases and hyperpigmentation problems.