The cancer research community has begun to address the in silico modeling approaches, such as quantitative structure-activity relationships (QSAR), as an important alternative tool for screening potential anticancer drugs. With the compilation of a large dataset of nucleosides synthesized in our laboratories, or elsewhere, and tested in a single cytotoxic assay under the same experimental conditions, we recognized a unique opportunity to attempt to build predictive QSAR models. Here, we report a systematic evaluation of classification models to probe anticancer activity, based on linear discriminant analysis along with 2D-molecular descriptors. This strategy afforded a final QSAR model with very good overall accuracy and predictability on external data. Finally, we search for similarities between the natural nucleosides, present in RNA/DNA, and the active nucleosides well-predicted by the model. The structural information then gathered and the QSAR model per se shall aid in the future design of novel potent anticancer nucleosides.