The study of the styrene–Ground Tire Rubber (GTR) graft radical polymerization is particularly challenging due to the complexity of the underlying kinetic mechanisms and nature of GTR. In this work, an experimental study on two scales (∼10 mL and ∼100 mL) and a machine learning (ML) modeling approach are combined to establish a quantitative relationship between operating conditions and styrene conversion. The two-scale experimental approach enables to verify the impact of upscaling on thermal and mixing effects that are particularly important in this heterogeneous system, as also evidenced in previous works. The adopted experimental setups are designed in view of multiple data production, while paying specific attention in data reliability by eliminating the uncertainty related to sampling for analyses. At the same time, all the potential sources of uncertainty, such as the mass loss along the different steps of the process and the precision of the experimental equipment, are also carefully identified and monitored. The experimental results on both scales validate previously observed effects of GTR, benzoyl peroxide initiator and temperature on styrene conversion but, at the same time, reveal the need of an efficient design of the experimental procedure in terms of mixing and of monitoring uncertainties. Subsequently, the most reliable experimental data (i.e., 69 data from the 10 mL system) are used for the screening of a series of diverse supervised-learning regression ML models and the optimization of the hyperparameters of the best-performing ones. These are gradient boosting, multilayer perceptrons and random forest with, respectively, a test R2 of 0.91 ± 0.04, 0.90 ± 0.04 and 0.89 ± 0.05. Finally, the effect of additional parameters, such as the scaling method, the number of folds and the random partitioning of data in the train/test splits, as well as the integration of the experimental uncertainties in the learning procedure, are exploited as means to improve the performance of the developed models.