Abstract: Non-Boussinesq model is established based on Boussinesq model and full buoyancy model, to simulate the natural convection flow in multi-fluid domains with high temperature difference. The comparison between predicted profiles and experimental data in a single-fluid domain and in multi-fluid domains with high temperature difference is conducted by implementing respectively Boussinesq model, full buoyancy model and Non-Boussinesq model. The results show that for single-fluid domain, the predicted velocity and temperature using Non-Boussinesq model and full buoyancy model coincide with the experimental data with average derivation less than 9%. Boussinesq model is less accurate in simulating the velocity in high temperature different region. For multi-fluid domains, accurate velocity profiles in all fluid domains are not guaranteed for the full buoyancy mode. However, developed Non-Boussinesq model can not only simulate precisely the buoyancy force caused by density variation, but also guarantee an acceptable velocity results for multi-fluid domains. The momentum source term analysis and CFD analysis in multi-fluid domains coincide well with each other. The buoyancy force model is with significant effect on the velocity profile in multi-fluid domain problem, but with little effect on temperature profile prediction. Hence, the prediction method used in this paper can be used in the natural convection prediction in multi-fluid domains with high temperature difference.