TC21 alloy is a new alpha–beta damage tolerance titanium alloy with high strength and high toughness. Little work has been done in the field of machinability analysis since this alloy was developed. The cutting forces and tool wear in high-speed milling of TC21 alloy with physical vapor deposition ((Ti, Al)N-TiN)-coated carbide tools under different cutting conditions were investigated in this article. The results showed that the cutting force component F _x was more dominant of the three components, and the cutting forces presented an increasing trend with the tool wear progress, which in turn deteriorated the cutting condition and accelerated the tool failure progress. The major tool wear modes in high-speed side-milling TC21 alloy with coated carbide were adhesion and chipping on the rake face along with chipping and transverse crack on the flank face. Moreover, there was obvious nose depression from both the rake face and the flank face. Chipping along the flank and rake faces was identified as the main factor responsible for the failure of the coated carbide tools during the milling of titanium alloy TC21.