The main objective of this study was to evaluate the effect of functionalized silica nanoparticles with Fe2O3, NiO, and MoO3 metal oxides on the decomposition of asphaltenes, through an experimental simplex–centroid mixture design for surface area, asphaltene adsorption, and activation energy. The experimental nanoparticle surface area was measured by adsorption of N2. Adsorption isotherms, and the subsequent oxidation process of asphaltenes, were performed through batch adsorption experiments and thermogravimetric analysis, respectively. Among the monometallic systems, the presence of iron increased the affinity between the nanoparticle and the asphaltenes, and a higher metal oxide load increased the adsorptive capacity of the system. For the pairings evaluated, there was better synergy between iron and nickel, with the participation of the former being slightly superior. In the mixture design that included three transition elements, the participation of molybdenum was not significant, and the adsorption of asphaltenes was dominated by the active sites formed by the other two transition element oxides. The mixture design created to minimize the activation energy showed that the interaction of the three transition elements is important and can be evidenced in the interaction coefficients.