Nine new 2-amino-4-substituted aryl-6-(2-methyl-1,8-naphthyridin-3-yl) nicotinonitriles (3a-i) have been synthesized from 3-acetyl-2-methyl-1,8- naphthyridine (1) by condensing it with a mixture of malononitrile and appropriate aromatic aldehydes in presence of ammonium acetate. Also, the compound (1), underwent smooth cyclocondensation when heated with a mixture of ethyl cyanoacetate and appropriate aromatic aldehydes in presence of ammonium acetate, to give nine new 4-substituted aryl-6- (2-methyl-1,8-naphthyridin-3-yl)-2-oxo–1,2-dihydropyridine-3-carbo-nitriles (4a-i). The compounds (3b) and (4c) have been also prepared from 1- (2-methyl-1,8-naphthyridin-3-yl)-3-substituted phenyl-prop-2-en-1-one (2) by condensation with malononitrile and ethyl cyanoacetate respectively. The intermediate chalcone (2) was conveniently obtained by the treatment of methanolic 3-acetyl-2-methyl-1,8-naphthyridine with 4-chloro benzaldehyde in presence of mixture of triethylamine (TEA) and diethylamine (DEA). The structures of compounds (3a-i) and (4a-i) were established on the basis of their elemental analysis and spectral (IR, 1HNMR & MASS) data. All the new compounds were subjected to in vitro antibacterial testing against four pathogenic strains and antifungal screening against three fungi. Results indicate some of them exhibited promising activities and they deserve more consideration as potential antimicrobials.