Grain refinement is an effective way to improve the comprehensive mechanical properties of titanium matrix composites. In this work, the strong grain refinement effect of GO on 600 ℃ high-temperature titanium alloy prepared by hot isostatic pressing was found. The refinement mechanism was studied by experimental analysis, first-principles calculation and cellular automaton simulation. The α grain size of the composite with 0.50wt.% GO decreased by 53.2% compared with the matrix alloy. The direct effect of GO on grain refinement was weak. GO introduced C and O as α-stable elements to increase α phase content, resulting in the solid solubility of Si decreasing and fine (TiZr)6Si3 particles precipitating. (TiZr)6Si3 particles prevented dislocation from moving to accelerate continuous dynamic recrystallization nucleation and pinned grain boundary to inhibit grain growth. The results of cellular automaton simulation show that the inhibitory efficiency of (TiZr)6Si3 on grain growth was 4.7 times that of GO. The unique mechanism that GO promoted silicide particles precipitation and indirectly refined grain provided a design route for novel titanium matrix composites synergistically strengthened by two-dimensional nanosheets, in-situ nanoparticles and grain refinement.