A series of 1-(1,3,4-thiadiazol-2-yl)methyl-1H-1,2,4-triazole derivatives were prepared and evaluated for their antifungal activities. The chemical structures of these compounds were determined by means of elemental analyses, (1)H NMR, and X-ray crystallography. Quantitative structure-activity relationship (QSAR) studies were performed on these compounds using physicochemical parameters as independent parameters and antifungal activity as a dependent parameter, where antifungal activity correlated best (r > 0.9) with hydrophobic parameters (pi) and indicator (H). Moreover, the results are interpreted on the basis of a multiple regression model. The model has been internally and externally validated. Furthermore, the domain of applicability which indicates the area of reliable predictions is defined.