To simulate the effects of hot working parameters on microstructure and flow resistance during dynamic recrystallization (DRX) of a Ni–Cr–Mo-based C276 superalloy, a 2D mesoscopic model has been established using cellular automaton (CA) method. The isothermal hot compression tests were performed on a Gleeble 1500 thermal-mechanical simulator at the temperature range of 1273–1473 K and strain rate range of 0.001–5 s−1. The flow stress behaviors were then obtained and the microstructures of quenching specimen were observed after compression. Then the dislocation density evolution, nucleation and grain growth during hot compression were determined from experiments and integrated to the CA model. The topology of microstructure evolution and deformation resistance were calculated using the developed CA model and compared with the experimental ones. The CA simulation results show reasonable agreements with the experiments, implying the developed CA can capture the effects of processing parameters on the DRX behavior of C276 superalloy.