This paper presents a study about a Machine Learning approach for modeling the stiffness of different high-modulus asphalt concretes (HMAC) prepared in the laboratory with harder paving grades or polymer-modified bitumen which were designed with or without reclaimed asphalt (RA) content. Notably, the mixtures considered in this study are not part of purposeful experimentation in support of modeling, but practical solutions developed in actual mix design processes. Since Machine Learning models require a careful definition of the network hyperparameters, a Bayesian optimization process was used to identify the neural topology, as well as the transfer function, optimal for the type of modeling needed. By employing different performance metrics, it was possible to compare the optimal models obtained by diversifying the type of inputs. Using variables related to the mix composition, namely bitumen content, air voids, maximum and average bulk density, along with a categorical variable that distinguishes the bitumen type and RAP percentages, successful predictions of the Stiffness have been obtained, with a determination coefficient (R2) value equal to 0.9909. Nevertheless, the use of additional input, namely the Marshall stability or quotient, allows the Stiffness prediction to be further improved, with R2 values equal to 0.9938 or 0.9922, respectively. However, the cost and time involved in the Marshall test may not justify such a slight prediction improvement.