In this paper, the evolutions of cutting force, cutting temperature, and surface roughness, and the corresponding machinability in asymmetric up-milling of TC25 alloy are investigated. The results indicated that radial depth of cut generated opposite influence on the cutting force/cutting temperature versus surface roughness. The reason can be accounted as the intertwining of feed marks at low radial depth of cut, and the mechanism of hard cutting at a high radial depth of cut. Moreover, the asymmetry has a significant effect on the machinability in asymmetry up-milling TC25 alloy. Changing the asymmetry, i.e., the radial depth of cut, can alter the machinability while maintain the balanced development of various indexes. The machinability reaches the best when the radial depth of cut is ae = 8 mm. The axial depth of cut and feed per tooth should be selected as large as possible to avoid work hardening and to improve machining efficiency in asymmetric up-milling TC25 alloy. The cutting speed should be controlled within Vc = 100–120 m/min to obtain better machinability. On the basis of this research, it is expected to find optimized milling parameters to realize high efficiency milling of TC25 alloy.