This study was conducted to compare the antioxidant, anticytotoxic, and anti-inflammatory properties of Euphorbia maculata ethanol extract with those of E. supina ethanol extract. 2,2-Diphenyl-1-picrylhydrazyl (DPPH) radical and superoxide scavenging activities of E. maculata at 50 μg/mL were 38.3 ± 3.7 and 21.5 ± 1.2%, respectively, whereas those of E. supina at the same concentration were 109.4 ± 0.9 and 59.5 ± 4.8%, respectively. Oxygen radical absorbance capacities of E. maculata and E. supina at 10 μg/mL were 14.70 ± 0.63 and 26.17 ± 1.36 nmol/mL Trolox, respectively. Cupric reducing antioxidant capacities of E. maculata and E. supina at 10 μg/mL were 10.22 ± 0.97 and 62.99 ± 5.28 nmol/mL Trolox, respectively. Total phenolic contents of E. maculata and E. supina at 50 μg/mL were 29.03 ± 0.14 and 87.89 ± 0.20 nmol/mL gallic acid, respectively. E. maculata and E. supina were reported to prevent supercoiled DNA breakage induced by peroxyl and hydroxyl radicals in a concentration-dependent manner, where protection against the supercoiled DNA breakage provided by E. supina was greater than that provided by E. maculata. E. maculata and E. supina at 100 μg/mL inhibited tert-butyl hydroperoxide-induced cytotoxicity in HepG2 cells by 49.4 ± 4.3 and 87.3 ± 4.5%, respectively. E. maculata and E. supina at 500 μg/mL inhibited lipopolysaccharide-induced nitric oxide production in RAW 264.7 cells by 63.1 ± 7.0 and 85.2 ± 1.6%, respectively. The antioxidant capacities including DPPH radical scavenging, superoxide scavenging, oxygen radical absorbance, and cupric reducing antioxidant activity were found to be highly correlated with total phenolic content (0.896 < r < 0.983, p < 0.01) and anticytotoxic activities (0.915 < r < 0.960, p < 0.01). However, the superoxide scavenging activity was not significantly correlated (r = 0.604, p > 0.05) with the anti-inflammatory activity. Thus, these findings demonstrated that the radical scavenging, anticytotoxic, and anti-inflammatory capacities of E. supina were more potent than those of E. maculata. Further studies are needed to elucidate the properties of polyphenolic constituents in E. supina responsible for these effects and the underlying mechanisms.