The automotive industry is increasingly focused on developing more energy-efficient and eco-friendly air-conditioning systems. In this context, CO2 microchannel gas coolers (MCGCs) have emerged as promising alternatives due to their low global warming potential (GWP) and environmental benefits. This paper explores the application of machine learning (ML) algorithms to predict the thermohydraulic performance of MCGCs in automotive air-conditioning systems. Using data generated from an experimentally validated numerical model, this study compares various ML techniques, including both linear and nonlinear regression models, to forecast key performance metrics such as refrigerant outlet temperature, pressure drop, and heat transfer rate. Spearman’s correlation was employed to develop performance maps, whereas the R2 and MSE metrics were used to evaluate the models’ predictive accuracy. The linear models gave around 70% forecasting accuracy for pressure drop across the gas cooler and 97% accuracy for refrigerant outlet temperature, whereas the nonlinear models achieved more accurate predictions, with an accuracy ranging from 71% to 99%. This implies that nonlinear regression generally performs better than linear regression models in assessing the overall thermohydraulic performance of microchannel gas coolers. This research brings forth new ideas on how ML methods can be applied to enhance efficiency and effectiveness in gas coolers, contributing to the development of more eco-friendly automotive air-conditioning systems.