With the widespread application of vortex tube in various fields, it becomes essential to quantitatively explore the separation effect of different fluids (natural fluids, hydrocarbons, etc.) within the vortex tube and to promote its utilization. A new approach has been developed in this study to establish quantitative models for predicting the thermal effects of different fluids in a vortex tube. These models are based on both the macro properties of the working fluid and micro molecular descriptor through a molecular scale. A dataset of 11 numerical simulation results of hydrocarbons and hydrofluorocarbons refrigerants is employed. Three operating conditions, 10 property parameters, and 115 molecular descriptors are screened and identified using random forest feature analysis. Two types of models (micro and macro) have been developed by employing artificial neural network (ANN) modeling techniques. In the result, four key influencing fluid property parameters (the specific heat ratio γ, the multiplication of heat capacity and the molar weight cp·M, the kinematic viscosity ν, and the thermal conductivity λ) and nine molecular descriptors in affecting the thermal effect are identified and respectively chosen as the input in the macro and the micro ANN model establishment. Both types of developed models show a high correlation coefficient (R > .999) and a comparatively low mean square error (MSE). When R600 is employed in the validation, most of the relative error is less than 10%, suggesting both types of models can work effectively in predicting the thermal effect for other fluid. The findings contribute to a deeper understanding of the thermodynamic effect of vortex tubes and provide a valuable tool for selecting and optimizing working fluids in various applications.