The utilization of low global warming potential (GWP) refrigerants is crucial for reducing greenhouse gas emissions. Among these alternatives for hydrofluorocarbons (HFCs), R290 stands out as a natural refrigerant with a low GWP value of 3. Therefore, it is beneficial to promote its widespread adoption and enhance the efficiency of compressors and their systems that utilize R290 to mitigate the greenhouse effect. The present study investigates and compares the thermodynamic performance and compression characteristics of a high-speed compressor employing R290 as a refrigerant with those of an R32 compressor. In contrast to previous studies, this paper presents a novel approach by developing validated the zero-dimensional (0-D) and three-dimensional (3-D) simulation model, along with experiments, to investigate the distribution of performance loss and suction-compression characteristics in high-speed R290 compressors. The results demonstrate that the R290 compressor exhibits superior volumetric efficiency, while excessive compression at high speeds leads to a noticeable reduction in indicated power. The combination of increased over-compression loss and motor loss at high speeds resulted in a 11.7% rise in input power, leading to an 8.4% decline in thermodynamic performance for the R290 compressor under standard heating compared to the R32 compressor.