Metallurgical characteristics in the machined surface layer can be modified due to suffering the localized thermo-mechanical stresses during high-speed machining. Plastic deformation is generated by the localized thermo-mechanical stresses. The depth of plastic deformation will then influence the functional performances and service life of the machined components. However, the available tool life is diminished due to rapid tool wear in machining titanium alloy. The tool wear induces additional thermo-mechanical stresses on the tool-workpiece interface, which results in deeper plastic deformation. This article proposed a prediction model of the plastic deformation depth induced by the coupled thermo-mechanical stress considering tool flank wear. The proposed model can effectively predict the depth of plastic deformation at different tool flank wear stages. This prediction model is verified with the high-speed turning experiments of Ti-6Al-4V. It is demonstrated that there is a better consistency between the measured and predicted results with the error interval of 11.2% to 15.4%. The results indicated that the tool flank wear should be limited in an appropriate value from the perspective of the depth of plastic deformation. This work can be used to guarantee the machined surface integrity during machining Ti-6Al-4V.