Based on theoretical simulations, the best design for obtaining AgPt nanostructures (nanoshells with hollow interior) was unraveled that could exhibit methanol tolerance for oxygen reduction reaction (ORR) that occurs during direct methanol fuel cells (DMFCs) operation. A theoretical investigation of Pt@Ag and Ag@Pt core-shell nanoparticles and AgPt nanoshells′ interaction with oxygen and methanol revealed that the oxygen interaction is significantly more favorable on AgPt nanoshells′ surface, hindering the methanol oxidation reaction (MOR) due to the random arrangement of Ag and Pt atoms. Experimentally, the nanoshells were prepared by a galvanic substitution and immobilized them onto silica, and the material was finely understood by associating electrochemical and physicochemical studies. Cyclic voltammetry showed the reduction and oxidation processes of the catalyst‘s species; however, XPS precisely showed that significant amounts of oxidized species were present (60.5 % of Ag0 and 39.5 % of Ag+, and 55.1 % of Pt0 and 44.9 % of Pt+2), which could affect the performance of the material. Indeed, the catalyst showed an excellent performance to ORR; the system yielded a 4-electron ORR mechanism with just 1.0 wt.% Pt loading, with significant stability after 1000 runs. In addition, Koutecky-Levich and Tafel plots assisted in understanding better the mechanism on the catalyst‘s surface, suggesting a first-electron transfer for the rate-determining step. Also, the catalyst resistance to the methanol crossover, theoretically simulated and predicted, was tested, showing remarkable tolerance for the alcohol up to a concentration of 2 M. Hence, a cathode catalyst with improved selectivity, low metal loading, high stability, and easy preparation was obtained.