In response to the poor wear resistance and high-temperature oxidation resistance of titanium alloys during service, a series of lightweight refractory high-entropy alloys (RHEAs) can be designed for the laser cladding coating of titanium alloy surfaces, with due consideration of the compositional and structural characteristics of titanium alloys. Firstly, the structural stability, mechanical and thermal properties of four lightweight RHEAs (MoNbTiV, AlMoNbTiW, CrMoNbTiV, and AlCrMoNbTiV) with equal atomic ratios were designed and calculated using first principles combined with quasi-harmonic approximation (QHA). The results indicate that all four RHEAs are stable BCC, exhibiting elastic anisotropy and ductility. The lightest density is 6.409 g/cm 3. Adding Al/Cr can cause structural distortion and affect its mechanical properties. Their Young’s moduli are in the following order: AlCrMoNbTiV > MoNbTiV > CrMoNbTiV > AlMoNbTiV. The thermal expansion coefficients of the four RHEAs and titanium alloys are very close, with a difference in linear expansion coefficient of less than 1.16 × 10 −5/K. Meanwhile, the metallurgical bonding of four types of RHEA coatings was successfully achieved on a Ti-6Al-4V(TC4) substrate through laser cladding technology, and all coatings exhibited a unique BCC solid solution phase.