Some new fused chromenopyrimidines have been synthesized and evaluated for their antimicrobial activity based on the precursor 4H-chromene-3-carbonitrile. Heterocyclization of 4H-chromene-3-carbonitrile derivative results in pyrimidine, pyrimidinone, pyrimidinedithione, and iminopyrimidine derivatives. Acetylated N-aminochromeno[2,3-d]pyrimidine derivative has been introduced into SN2/heterocyclization reaction with formation of 2-substituted pyrimidinone derivatives. 4H-Chromene-3-carbonitrile propargylation followed by the “click reaction” has resulted in chromene linked 1,2,3-triazole. Some newly synthesized compounds demonstrate significant antimicrobial activity.