An efficient and smart approach for design and synthesis of a novel series of nicotinonitrile-1,2,3-triazole-acetamide hybrids was described. The synthetic methodology was commenced with preparation of acetylene derivatives via alkynylation of 2-oxonicotinonitrile with propargyl bromide under mild basic catalyst (pot. carbonate). The facile click cycloaddition reaction of alkynes 2a-f and azido-acetamides 3-5 in the presence of catalytic Cu(I) in H2O/tetrahydrofuran (THF) was utilized for the synthesis of target molecules 6a-l. Triazoles 6c, d, f, and 6i have highly activity against the four pathogenic bacteria (Escherichia coli, Pseudomonas aeruginosa, Bacillus subtilis, and Staphylococcus aureus) and two pathogenic fungi (Candida albicans and Aspergillus flavus) with minimum inhibitory concentration (MIC) in between 0.5 and 4 μg/ml for bacteria and 0.5 and 8 μg/ml for fungi.