The refrigerant used in heat pumps significantly influences the overall system performance. However, selecting a proper refrigerant is no trivial matter due to the heat pumps’ sensitivity to the selected flowsheet, components, and operating conditions. Herein, a holistic approach is used that covers all these interdependencies simultaneously considering the flowsheet, fluid‐dependent compressor efficiencies, and the operating point. Six low global warming potential (GWP<150) refrigerants are investigated, which include pure fluids, azeotropic mixtures, and zeotropic mixtures from different substance groups. For four flowsheets, the seasonal coefficient of performance (SCOP) by EN 14825 is calculated and serves as the assessment metric. The case study is based on typical conditions of residential heat pumps. The results show that the SCOPs substantially differ depending on the refrigerant and the flowsheet (reaching from 3.8 to 4.6). Differences in the performance of refrigerants for an equal flowsheet are mainly driven by compressor efficiency. However, these differences can be overcome by adjusting the flowsheet. In particular, when an internal heat exchanger is added, the refrigerant ranking is substantially changed. It is shown that R436A, which is inferior to R290 for the basic cycle, benefits more from an internal heat exchanger and reaches a competitive SCOP than R290.