Fabrication of sintering- and carbon-free Ni catalysts for methane dry reforming (MDR), which is attractive to upgrade greenhouse gases CH4 and CO2, 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 CH4 and CO2 of 6.98 and 7.16 mmol/(gNis), respectively, at 1023 K for 50 h. The rates were 2-3 times enhanced compared to those in the literature. XRD, TEM, H2-TPR, and so forth revealed that the alloy effect, size effect, and MSI of Ni-Cu and CeO2 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 SiO2 nanospheres realized sintering-free alloys and CeO2 nanoparticles. The synergistic approach provides a universal strategy for sintering- and carbon-free Ni catalyst design for MDR reaction.