The flow behavior and microstructural evolution of a high-density Ni-42W-10Co-1Mo (wt.%) alloy were investigated at 1150-1300°C under strain rates of 0.001-1s_^-1 using a Gleeble-1500D. The results show that the initial microstructure was compsed of face-centered cubic matrix and σ phase. The flow stress was sensitive to the deformation temperature and strain rate, and the stress-strain curve showed a typical dynamic revertive softening characteristics deformated 1150°C, while typical dynamic recrystallization softening characteristics were observed deformed at 1200-1350°C. The Arrhenius equation was established based on the stress-strain curves, and the hot deformation activation energy of the Ni-42W-10Co-1Mo alloy was calculated to be 446.2 kJ/mol. The thermal processing map was constructed based on the dynamic material model to evaluate the thermal processing performance, and the instable zone was located at 1300°C under high strain rate. The deformation microstructureal evolution revealed that the dynamic recrystallization mechanism was discontinuous dynamic recrystallization, which preferentially nucleated around the σ phase. Finally, the optimized hot working window for Ni-42W-10Co-1Mo alloy was deformed at 1250-1300°C under strain rate of 0.1-0.01s_-1^.