A series of 1-(1H-1,2,4-triazol-1-yl)-2-(2,4-difluorophenyl)-3-substituted-2-propanols (1a-o), analogues of fluconazole, were designed based on computational docking to the active site of cytochrome P450 14α-demethylase (CYP51) and synthesized for the first time using a click reaction. Their structures were characterized by ¹H NMR, ¹³C NMR, and HRMS. The in vitro antifungal activities of all target compounds were evaluated against eight human pathogenic fungi, showing that all were active to some extent (except against Aspergillus fumigatus). Most compounds exhibited higher activities against Candida albicans SC5314 and C. albicans Y0109 than all six positive controls. Compound 1k had an MIC80 value 32 times lower than that of fluconazole (FCZ) against C. alb. SC5314 and 64 times lower against Candida kefyr. Compound 1o had an MIC80 value 8 times lower than FCZ against C. alb. SC5314, 16 times lower against C. kefyr, and 32 times lower against Trichophyton rubrum, with activity comparable to itraconazole for most fungi tested. Docking studies proposed a likely binding mode for 1k: the triazole interacts with heme iron, the 2,4-difluorophenyl group occupies a hydrophobic pocket, and the side chain forms π-π stacking with Phe380 and interacts with another hydrophobic pocket. In conclusion, an efficient click reaction method was developed for synthesizing these novel triazole derivatives, which exhibited excellent broad-spectrum antifungal activity. Introducing the 1,2,3-triazole group and substituted benzyl side chains was beneficial for activity, and compounds 1k and 1o are worthy of further study as potential new antifungal drugs.