High-entropy ceramics (HECs) are novel materials with unexpected chemistry. However, HEC-based catalysis or chemistry has rarely been studied before. Herein, porous high-entropy MgAl 2 O 4 (HE-MgAl 2 O 4 ) (up to denary metals: Mg, Ti, V, Cr, Mn, Fe, Co, Ni, Cu, and Zn) was prepared (S BET = 139 m 2 /g). The synthetic chemistry, the tolerance law of different metals, and the thermodynamic rule for crystallization have been well studied. The comparison of binary-, ternary-, quaternary-, quinary-, and denary-MgAl 2 O 4 highlighted the key role of entropy, which forces cations with intrinsic different radii to occupy similar sites of spinel. Interestingly, high entropy naturally endows the HE-MgAl 2 O 4 catalyst with exceptional stability even when operated at high-temperature moisture (350°C) for 24 h. Then, ab initio molecular dynamics studies proved that the thermal stability of HE-MgAl 2 O 4 originated from the entropy stabilization effect and kinetically stabilized structure. Moreover, CH 4 oxidation with 10 vol % steam in feeding gas was performed, and the pristine activity was preserved by the HE-MgAl 2 O 4 catalyst over continuous operation (600°C, 100 h). • The synthetic chemistry of high-entropy ceramics was studied • The entropy-driven force can incorporate up to ten different elements into MgAl 2 O 4 • Exceptional moisture-resistance of MgAl 2 O 4 was observed • AIMD study of the thermodynamically stability of high-entropy ceramics was performed By exploring synthetic chemistry for high-entropy ceramics via experiments and theory calculations, this work offers a fundamental understanding of the design of porous high-entropy materials. By incorporating ten different transition metals into a MgAl 2 O 4 spinel, we highlight the key role of entropy for lowering Gibbs free energy. Moreover, this study shows the excellent moisture-resistance properties of high-entropy MgAl 2 O 4 spinels during CH 4 oxidation, which reveals that high-entropy ceramics can be a reliable catalyst or support in the real world. In this work, we report the preparation of a porous high-entropy MgAl 2 O 4 -type spinel (up to denary metals: Mg, Ti, V, Cr, Mn, Fe, Co, Ni, Cu, and Zn) that exhibits brilliant activity and compelling stability for methane oxidation. The relationship between entropy and enthalpy is discussed, and the key role of entropy is highlighted. This work provides fundamental insights into the rational design of advanced high-entropy materials.