The aim of this study is to design and develop an efficient leaching process based on a fundamental and theoretical thermodynamic analysis and the optimization of the operation parameters via the response surface methodology (RSM). Using this methodology, the design of a leaching process for the recovery of copper, silver, and lead from highly metal-concentrated fractions of e-waste is presented. Thermodynamic predictions were performed through the construction and analysis of Pourbaix diagrams for the specific conditions of the leaching system. From this analysis, it was possible to determine the values of potential (E vs NHE) and pH at which the leaching reactions occur spontaneously. Additionally, RSM was useful to deduce a quadratic semiempirical model that predicts the copper leaching efficiencies as a function of two parameters involved in the leaching procedure, the stirring speed and the solid/liquid ratio, by which the response variable, the leaching efficiency, can be optimized.