The thermomechanical coupling simulation of the isothermal equal channel angular pressing (ECAP) of Ti-6Al-4V alloy was conducted. The effect of processing parameters, ECAP pass number and the residual billet on the effective strain, stress and temperature distribution was investigated. Based on the coupling simulation results, it is found that the shear factor, ram speed, deformation temperature, channel intersection angle and residual billet significantly affect the ECAP deformation behaviors. Meanwhile, the experimental study of the isothermal ECAP process of Ti-6Al-4V alloy using route C, in which the repeated rotation angle around the longitudinal billet axis before reinsertion in the die was 180°, were conducted at a deformation temperature of 750°C, a ram speed of 0.3 mm⋅s −1 , an outer arc of curvature of 60° and a channel intersection angle of 120°. Furthermore, a large amount of recrystallization occurs and some prior α phase grains grow in the post-ECAP process of Ti-6Al-4V alloy. The yield strength of post-ECAP Ti-6Al-4V alloy increases compared with that of as-received Ti-6Al-4V alloy.