Reducing the hot working temperature and high-temperature deformation resistance of titanium alloy to improve hot rolling and hot extrusion workability of products with thin walls and complex section shapes has always been an important topic in the field of titanium alloy processing. This paper proposed a strategy of adding Mo and Fe elements to simultaneously reduce the hot working temperature and high-temperature deformation resistance of Ti-6Al-4V alloy. The effects of Mo and Fe contents on the microstructure, β transus temperature (T_β), and high-temperature flow stress (HFS) of Ti-6Al-4V-xMo-xFe (x=0−5) alloys were investigated. The results showed that adding Mo and Fe can substantially reduce the T_β and HFS of the alloy, and greatly improve its room-temperature strength. Compared with commercial Ti-6Al-4V samples, the T_β of Ti-6Al-4V-2Mo-2Fe and Ti-6Al-4V-3Mo-3Fe samples was decreased by 68−98 °C, and the HFS at 800−900 °C was decreased by 37.8%−46.0%. Compared with hot-rolled Ti-6Al-4V samples, the room-temperature tensile strength of hot-rolled Ti-6Al-4V-2Mo-2Fe samples was increased by about 30%, while the elongation hardly decreased. The increased strength was mainly attributed to fine grain strengthening and solid solution strengthening. The hot workability and room-temperature strength of Ti-6Al-4V alloy can be significantly improved by adding 2−3 wt.% Mo and Fe simultaneously.