After benchmarks on pyrazolo[1,5-a][1,3,5]triazin-2-thioxo-4-ones, we carried out B3LYP density functional theory computations on the structure and vibrational spectroscopy of a series of twenty-one of its derivatives exhibiting various extent of inhibitory activity against thymidine phosphorylase (TP). Then, we performed drug-like calculations, quantitative structure-activity relationship (QSAR) modeling and an evaluation of the physicochemical properties of this series. In order to design the relationships between molecular descriptors and TP inhibition by pyrazolo[1,5-a][1,3,5]triazin-2-thioxo-4-ones derivatives, we used a multiple linear regression (MLR) procedure. A QSAR model is predicted. A further external set of molecules was used for validation where a high correlation between experimental and predicted activity values is noticed.