A new series of (E)-3-(3-(4-substituted phenyl)-1-phenyl-1H-pyrazol- 4-yl)-1-(2-hydroxy-4-((1-aryl-1H-1-2,3-triazol-4-yl)methoxy)phenyl)- prop-2-en-1-one derivatives was synthesized. The synthesis of the title compounds involved the 1,3-dipolar Cu(I)-catalyzed alkyne–azide cycloaddition (CuAAC) reaction of (E)-3-(3-(4-substituted phenyl)-1-phenyl-1H-pyrazol-4- -yl)-1-(2-hydroxy-4-(prop-2-yn-1-yloxy)phenyl)prop-2-en-1-ones with aromatic azides. The structures were confirmed by NMR, FT-IR, mass and elemental analysis. All the synthesized compounds (6a–j) were evaluated for their antimicrobial activity. Compounds 6a, 6d and 6e demonstrated promising inhibitory effects on both bacterial and fungal strains.