In order to study the changes of the microstructure and properties for titanium alloy TC18 in the isothermal high-temperature compression process, the isothermal high-temperature compression experiment was carried out by Gleeble-1500 thermal simulation testing machine, and the axial compressive expansion coefficients of all specimens were calculated to be greater than 0.9. Therefore, the validity of the thermal compression test was verified. Then, the influences of different deformation temperatures and strain rates on mechanical properties and microstructure changes were researched by variable-control method. The results show that the flow stress of titanium alloy TC18 decreases with increasing of deformation temperature, and increases with increasing of strain rate in the isothermal high-temperature compression process. However, with increasing of temperature and strain rate, the primary equiaxed α-phase and secondary acicular α-phase gradually disappear due to phase change, while the β phase gradually grows and forms coarse grains with two kinds of softening mechanisms of dynamic recovery and dynamic recrystallization.