Isobutane dehydrogenation is a vital route for the production of isobutene, an important substance for methyl tert-butyl ether. However, the reaction is typically performed at relatively low pressure and high temperature, resulting in a facilitated coke formation. Here, we used rare-earth metals (Y, La, Ce) as dopants to modify the ZnAl2O4 support and studied their effects on Pt-Sn catalyzed dehydrogenation of isobutane. Combining the experimental and theoretical results, it is demonstrated that while Y and La tend to incorporate into the matrix of ZnAl2O4, separate CeO2 phase could be easily formed on ZnAl2O4 surface, leading to a decrease in both amount and strength of the Lewis acid sites. And for the La-ZnAl2O4, because of the large local deformation, oxygen vacancy can be readily formed, and results in a lot acid sites in the subsurface layer available for reactions. Deactivation rates of the catalysts in isobutane dehydrogenation is found to linearly correlate with the Lewis acid amounts over the modified supports. Compared with the catalysts of Pt-Sn/ZnAl2O4, Pt-Sn/La-ZnAl2O4 and PtSn/Y-ZnAl2O4, Pt-Sn/Ce-ZnAl2O4 exhibits superior catalytic performance due to the low coke contents and high Pt dispersion. These results may provide additional insights on the design and optimization of isobutane dehydrogenation catalysts by tailoring the composition and structure of oxide supports.