Flavonoids are the most common group of polyphenolic compounds in the human diet including fruits, vegetables, nuts and plant derived beverages, tea and wine. These compounds have been reported to possess a wide range of bio-activities. Structural variations of these flavonoids are associated with many different biological and pharmacological activities including antioxidant, anticancer, antiinflamatory, antihyperglycemic, antidiabetic, antibacterial, antifungal and antiviral activities. Antioxidant enzymes as well as non enzymatic antioxidants are the first line of defense against oxidative stress. This oxidative stress is the underline mechanism for diabetic complications. In recent years, the high therapeutic properties of flavonoids and their analogues have brought attention of chemists to synthesize various kinds of their derivatives by improving the existing synthetic methodologies.It is therefore, the aim of present study was to synthesis and characterize the novel flavonoids and their derivatives. These compounds were screened for their antioxidants potential and evaluate their antihyperglycemic activity. By using Claisen−Schmidt condensation, 2,5-dihydroxyacetophenone was allowed to condense with different aromatic aldehydes. Four kinds of products were isolated; chalcones (105, 106, 108, 110, 115, 119, 121), flavanones (107, 109, 111, 120, 123), Arylmethylidene flavanone (112, 113, 114, 116, 117, 118, 122, 124, 127, 128) and 2-Arylmethylidene indanones (125, 126). A series of chalcones (131-135) was also synthesized by reacting 2 hydroxy-5-nitro acetophenone with different aromatic aldehydes. The synthesized chalcones 134 underwent cyclization in the presence of iodine to obtain compound 136. Compound 105 was reacted with hydrazine hydrate to obtain 2-(5-(2-nitrophenyl)4,5-dihydro-1H-pyrazol-3 yl)benzene-1,4-diol (129) and compound 108 was reacted with hydrazine hydrate to form 2 (5-(4-nitrophenyl)-1-phenyl-4,5-dihydro-1H-pyrazol-3-yl)benzene-1,4-diol (130). The compound (125) was reacted with different N-substituted-2-bromoacetamide (137-139) to form compound (144-146). After reacting 8-acetyl-7-hydroxy-4-methylcoumarin (142) with 2′-Bromo-N-benzylacetamide (137), the product 2-[(8-acetyl-4-methyl-2-oxo-2H-chromen 7-yl)-oxy]-N-phenylacetamide (143) was obtained. All the synthesized compounds were characterized and confirmed through spectroscopic analysis i.e., Fourier-transform infrared spectroscopy (FTIR), Nuclear magnetic resonance (NMR) spectroscopy and Electron Ionization Mass Spectrometry (EIMS). The compounds 105-126, 129, 130 and 131-135 were checked for their antioxidant potential by α, α-diphenyl-β-picrylhydrazyl (DPPH) free radical scavenging, Iron chelating activity, Iron chloride (FeCl3) reducing power activity, Phosphomolybdinum assay and 2,2′ azinobis-(3-ethylbenzothiazoline-6-sulfonic acid) (ABTS) activity. Among all the synthesized compounds, the chalcones 105, 106, 108, 110, 115, 119, and 121 showed excellent antioxidant activity. The chalcones 105, 110 and 115 exhibited better antioxidative behavior than trolox and ascorbic acid. The Oral glucose tolerance test (OGTT) was performed in normal hyperglycemic rats for compounds 105, 106, 107, 108 and 109. The compound 109 exhibited good activity in normal hyperglycemic rats while the compound 105 showed significant activity in streptozotocin (STZ) induced diabetic rats as compared to reference Glabenclamide. For in silico studies, Quantitative Structure-Activity Relationships (QSAR) were performed for compounds 105-126 and 131-135. The comprehensive intra molecular charge transfer has been perceived from the highest occupied molecular orbitals (HOMOs) to the lowest unoccupied molecular orbitals (LUMOs). The smaller ionization potential (IP) and bond dissociation energy (BDE) values for compound 105, 106, 107, 108 and 109 revealed that these compounds would show proficient antioxidant behavior which is in good agreement with the antioxidant experimental data. Experimental and computational investigations concluded that compound 105 might be an effective antihyperglycemic agent because of its antioxidative nature and smallest ionization potential.