Thermoplastic polyurethanes (TPUs) are characterized by their unique elastic and thermoplastic properties, which make them indispensable for a wide range of applications in industry. The present study focuses on investigating the interactions of TPUs with oils and fuels, particularly on the analysis of sorption mechanisms and the role of chemical structure for material compatibility. Two TPUs with different soft segments, ether-based and ester-based, were tested for their compatibility with these media. The influence of the structural composition on material compatibility was demonstrated by combining sorption tests with mechanical and chemical analyses. It was found that ether-based TPUs have a higher absorption and diffusion rate of non-polar media, indicating worse compatibility with these substances. In addition, aromatics were found to be preferentially absorbed by the TPUs, with those based on ester having a higher affinity for these compounds due to stronger polar interactions. These results provide important insights for developing chemically resistant TPUs that should retain their mechanical and elastic properties. By precisely controlling these interactions, TPUs can be used more effectively in demanding environments, leading to improved performance and extended applicability of TPU-based products.