The composition−property relationship of 18 quaternary high entropy diborides (HEBs) consisting of boron and IVB, VB and VIB transition metals (TM) was investigated using first-principles calculations. A valence electron concentration−relative electronegativity (VEC−REN) composite descriptor was developed to effectively predict the mechanical properties of HEBs. The results demonstrate that with a fixed VEC, the rise of the REN makes HEBs harder but more brittle when the electronegativity of doped TM atoms is lower than that of boron atoms. However, HEBs become softer and more ductile as REN increases if the doped TM atoms have higher electronegativity than boron atoms. The VEC−REN composite descriptor can accurately classify and predict the mechanical properties of HEBs with different components, which provides important theoretical guidance for the rapid design and development of novel high-entropy ceramic materials.