The heaters working with supercritical fluids normally suffer from high temperature, high pressure and non-uniform heating, which would lead to thermal fragile and stress failure in practical engineering. However, efficient and accurate methods to predict the comprehensive stress in non-uniformly heating tubes are missing. Besides, to reduce the comprehensive stress, a criterion is required to provide optimization guidance of non-uniformly heating tubes. In present study, the thermal and mechanical performances of three typical non-uniformly heating tubes are numerically investigated using the FVM-FEM method. A generalized thermal deviation factor (GTDF) is then proposed. The results showed that the GTDF can accurately predict the ratio of comprehensive stress to yield strength and GTDF > 1 indicates the plastic deformation, which is much more convenient and efficient than the conventional structural analysis. Based on the GTDF, two methods of reducing heat flux non-uniformity and enhancing tube-inside heat transfer are proposed to reduce the comprehensive stress. The results show that the unilaterally elliptic dimpled tube reduces the maximum comprehensive stress by 30.8% compared with the smooth tube and also prevents the stress concentration in the dimple zone, which can be employed to reduce the comprehensive stress in various tubes under non-uniformly heating conditions.