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Chronic exposure of supraphysiologic glucose concentration to cells and tissues resulted in glucose toxicity which causes oxidative stress. Antioxidants have promising effect in suppressing the oxidative stress in the pathogenesis of diabetes mellitus (DM). Condensation of 2,5-dihydroxyacetophenone with different nitrobenzaldehydes was used to synthesize antioxidant nitro substituted chalcones along with nitro substituted flavanones in one step protocol. The compounds were characterized by IR, 1H NMR and 13C NMR and then screened for their in vitro antioxidant and in vivo antihyperglycemic activities. Postulated structures of the synthesized compounds were in agreement with their spectral data. The results indicated that the novel compound (2E)-1-(2,5-Dihydroxyphenyl)-3-(2-nitrophenyl) prop-2-en-1-one (2a) was potent antioxidant because of its lower IC50 value compared with trolox and ascorbic acid. Compound 2a also exhibited excellent antihyperglycemic activity in diabetic rats while the compound (E)-1-(2,5-Dihydroxyphenyl)-3-(4-nitrophenyl)prop-2-one (2c) suppressed the hyperglycemia more effectively in normal rats. The radical scavenging activity behavior was elucidated on the basis of hydrogen atom transfer and one-electron transfer mechanisms by density functional theory (DFT). The compound 2a showed the smallest ionization potential and bond dissociation enthalpy. Experimental and computational investigations concluded that compound 2a might be an effective antihyperglycemic agent because of its antioxidative nature and smallest ionization potential.