Fabrication of sintering-and carbon-free Ni catalysts for methane dry reforming (MDR), which is attractive to upgrade greenhouse gases CH 4 and CO 2 , is challenging. In this work, we innovatively synthesized Ni−Cu alloy nanoparticles confined by physical encapsulation and chemical metal−support interaction (MSI); the synergism of alloy effect, size effect, MSI, and confinement effect in the catalysts gave high rates of CH 4 and CO 2 of 6.98 and 7.16 mmol/(g Ni s), respectively, at 1023 K for 50 h. The rates were 2− 3 times enhanced compared to those in the literature. XRD, TEM, H 2 -TPR, and so forth revealed that the alloy effect, size effect, and MSI of Ni−Cu and CeO 2 enhanced the MDR activity; MSI promoted the ceria surface lattice oxygen mobility and generated more oxygen vacancies, almost completely gasifying carbon deposits; chemical confinement from MSI and physical confinement from SiO 2 nanospheres realized sintering-free alloys and CeO 2 nanoparticles. The synergistic approach provides a universal strategy for sintering-and carbon-free Ni catalyst design for MDR reaction.