High-entropy design for MgAl2O4 spinel has rarely been reported. In this study, six novel high-entropy spinel-structured (HES) MAl2O4 ceramics were prepared through the conventional solid-state reaction method. The effect of high-entropy design on the crystal structure, microscopic morphology, and microwave dielectric performance of HES ceramics was investigated based on X-ray diffraction (XRD), Raman spectra, and scanning/transmission electron microscopy (SEM/TEM). The analysis shows that the difference of one element among the high-entropy components can lead to an obvious variation in the lattice parameters, microstructures, and performance. The differences in microstructure, especially grain size, are the joint effects of particle size distribution, porosity and composition. Specifically, (Mg0.2Mn0.2Co0.2Ni0.2Zn0.2)Al2O4 (HES04) ceramic sintered at 1625 °C for 4h exhibits superior properties: εr=8.78 ± 0.03, Q×f=34,022 ± 910GHz (@12.62GHz), and τf=−29.3 ± 0.6 ppm/°C. These results suggest that the high-entropy strategy is an effective method to tune the dielectric properties of MgAl2O4 ceramic.