A series of novel 3-(1,2,4-triazol-1-yl)flavanones were synthesized based on the N-phenethylazole pharmacophore of azole antifungals. The results of antifungal assay revealed that 4'-fluoroflavanone derivative 4c exhibited the best profile of activity against Candida and Saccharomyces strains. Compound 4c was 4-16 times more potent than reference drug fluconazole against Candida albicans and Saccharomyces cerevisiae. The molecular docking study with lanosterol 14α-demethylase, in silico toxicity risks and drug-likeness predictions were used to better define of title compounds as antifungal agents. The favorable drug-like property of compound 4c makes 3-(1,2,4-triazol-1-yl)flavanone prototype as a promising lead for the future development of azole antifungal agents.