This work presents an approach to the contextual integration of fluid selection and compressor design for the cycle design of efficient industrial heat pumps. The vapor-compression cycle of an air–water heat pump operated at 42 °C source and 82 °C target temperature is investigated as a theoretical case study. An optimization study is performed, which includes the assessment of suitable refrigerants. Besides well-known single-component refrigerants, various binary mixtures are considered. The cycle optimization aims at simultaneously providing high cycle coefficient of performance and volumetric heating capacity. Cycle operation with the mixtures R-41/trans-2-butene (10, 90 mol. %) and CO2/R-161 (40, 60 mol. %) yields the highest values of these parameters, respectively. For further evaluation, centrifugal compressors operated with each of the two promising mixtures are designed with an in-house meanline program. In addition, the compressor design for the hydrofluoro-olefin refrigerant R-1234ze(Z) is considered as a reference. All designs are reviewed with respect to cycle as well as compressor design criteria and the applied methodology will assist designers in identifying key decision variables. The comprehensive design assessment suggests that CO2/R-161 (40, 60 mol. %) provides the best overall solution for an efficient cycle with a compact compressor design.