The microstructure evolution of wrought GH720Li alloy with three different initial grain sizes during isothermal hot deformation was studied. Grain size finer than ASTM 6.5 is considered to be the key critical initial condition for the final fine-grain grain structure, and a wider hot deformation window is found for the initial grain size with ASTM 10 or higher. The obvious effect of initial grain size on hot flow behavior is observed. The coarser the grain structure, the greater the hot flow behavior of the alloy. Discontinuous and continuous dynamic recrystallizations play important roles for the alloy with the initial ASTM 3 grain size The alloy with the initial grain size coarser than ASTM 6.5 are mainly subjected to discontinuous dynamic recrystallization. Dynamic recrystallization and superplastic deformation mechanism play important roles for the alloy with the initial ASTM 10 grain size. The hot working window of GH720Li alloys with ASTM 6.5 and ASTM 10 grain size was further determined for the final uniform fine grain structure.