The exploitation of high-entropy rare-earth monosilicates (HEREMSs) with enhanced calcium-magnesium-aluminum-silicate (CMAS) corrosion resistance is vital for their potential applications as environmental barrier coatings (EBCs). Here, we present an inverse design strategy to explore HEREMSs with superior CMAS corrosion resistance. By high-throughput synthesis and dissolution experiments of equimolar 1–12-cation apatite powders at 1400 ℃, four optimized rare-earth elements, Lu, Yb, Er, and Nd, are determined to compositionally screen preferable high-entropy apatite with the lowest dissolution rate in CMAS melt, ultimately facilitating the inversely design of novel (Nd_2/15Er_3/5Yb_2/15Lu_2/15)₂SiO₅ (HEREMS-1). Further CMAS corrosion experiments have verified its superior CMAS corrosion resistance at temperatures up to 1500 ℃, exceeding the performance of previously reported EBC materials. Our work paves an alternative way for developing HEREMSs with exceptional CMAS corrosion resistance, making them highly suitable for future EBC applications.