High temperature quasi-static compression test and RT dynamic compression tests on TC6 titanium alloy samples with 4 kinds of original microstructures were carried out using the gleeble-1500-type thermal simulation testing machine and Hopkinson bar. Effects of different original microstructures on their microstructure evolution in high temperature deformation, thermal distortion behavior and mechanical properties of TC6 alloy were studied, by combining the corresponding transmission electron microscope (TEM) analysis and the stress-strain curves. Results show that there exist two types of microstructure evolution for the 4 kinds of microstructures of TC6 alloy in the hot deformation. One type is equiaxed-type microstructure evolution, whose process is elongation of equiaxed α phase—dynamic recrystallization—growth of dynamic recrystallized grain—phase transformation of α/β. The other is lamellar-type microstructure evolution, whose process involves bending of lath-shaped α phase—breakdown of the lath-shaped α phase—dynamic recrystallization—growth of dynamic recrystallized grain—phase transformation of α/β and lath-shaped α phase becoming short-bar α phase. Dislocation movement and dynamic recrystallization are important factors that control microstructure evolution and mechanical properties of TC6 alloy during high temperature deformation. Lamellar structure shows the highest flow stress among the 4 kinds of microstructures due to its large quantity of grain boundaries which obstruct the dislocation movement. The equiaxed structure displays the lowest flow stress in the 4 kinds of microstructures owing to its larger grain size which involve lesser obstacles to movement of dislocation. The flow stresses of the binary and the solution and aging structure are between that of lamellar structure and that of the equiaxed structure because of their mixed construction of equiaxed grains and acerose grains. The room temperature dynamic mechanical properties of the TC6 alloy with 4 kinds of microstructures are sensitive to strain-rate. According to sort in descending, the plasticity of the 4 types of microstructures of TC6 alloy is equiaxed, binary, solution and aging, lamellar in turn and the flow stress of them is solution and aging, binary, lamellar, and equiaxed in turn, respectively, under the condition of dynamic compression with strain-rate from 2500 s-1 to 4000 s-1.