• Single-phase formation abilities of 120 two-component metal (transition metal and rare earth metal) diborides (TCBs) are studied by first-principles. • The thermodynamic stability of single-phase high-entropy transition and rare-earth metal diborides (HE TMREB 2 s) were quantified using the energy distribution of the local mixing enthalpies of all possible configurations. • HE TMREB 2 s were predicted to be enthalpy-stabilized materials, i.e., mixing enthalpy plays a critical role in single-phase stability. • The experimental results confirmed that enthalpy dominates the thermodynamic domain and drives the stability of REB 2 s in HE TMREB 2 s. Transition metal diborides (TMB 2 s) are the materials of choice in extreme environments due to their excellent thermal and chemical stabilities. However, the degradation of oxidation resistance of TMB 2 s at elevated temperature still hinders their applications. To cope with this challenge, it is effective to incorporate rare earth elements to form high-entropy transition and rare-earth metal diborides (HE TMREB 2 s). To obtain thermodynamically stable single-phase structures for HE TMREB 2 s, a “16 × 16 mixed enthalpy matrix” is constructed using first-principles calculations to predict the single-phase formation ability of 120 two-component diborides (TCBs). Through the use of the “16 × 16 mixed enthalpy matrix” of TCBs, specific combinations of TMB 2 s and REB 2 s that are most likely to form single-phase HE TMREB 2 s are confirmed. Subsequently, based on the energy distribution of the local mixing enthalpies of all possible configurations, the enthalpy and entropy descriptors of HE TMREB 2 s (RE = Sc, Lu, Tm, Er, Ho and Dy) are investigated. It is found that the mixing enthalpy plays a critical role in the stability of the single-phase HE TMREB 2 s, i.e., HE TMREB 2 s are enthalpy-stabilized materials. The experimental results further confirm that enthalpy dominates the thermodynamic domain and drives the stability of REB 2 s in HE TMREB 2 s. This study validates that enthalpy-stabilized HE TMREB 2 s can further expand the compositional space of ultrahigh temperature ceramics (UHTCs) and is expected to further improve the oxidation resistance and high temperature properties of UHTCs.