TC21 is widely used in the aerospace field, but it has properties such as low thermal conductivity, small elastic modulus, and high chemical activity. It causes severe tool wear, reduces tool life, and affects machining accuracy during milling. In this paper, the milling force and the tool wear mechanism on milling TC21 under three different cooling conditions (dry milling, HPAC milling, and MQL milling) are experimentally investigated. The variation of milling force under three lubrication conditions was analyzed, and an empirical prediction model of milling force was established by regression analysis of the experimental data. The relationships between milling force and milling speed, feed per tooth, axial cut depth, and radial cut depth were quantitatively described by this model. Meanwhile, the effects of milling parameters on milling forces under three lubrication conditions were analyzed. Experiments were performed to obtain the tool wear mechanisms under three lubrication conditions. Dry milling and HPAC milling have the same wear mechanism of tool surface: abrasive wear, adhesion wear, diffusion wear, and oxidative wear. They exist simultaneously and interact with each other. However, the tool wear is significantly reduced under HPAC condition, while the tool wear is mainly due to abrasive wear under the MQL condition. Tool wear curves were plotted for three experimental conditions, and the effects of tool wear on milling force were analyzed. The tool wear and milling force are best with MQL under three cooling conditions, which indicated that the introduction of MQL is suitable for the machining of TC21.