Heat pumps (HPs) are being developed with a new emphasis on cold climates. To lower the environmental impact of greenhouse gas (GHG) emissions, alternate low global warming potential (GWP) refrigerants must also replace the exclusive use of the refrigerant R410A, preferably without re-engineering the mechanical hardware. In this paper, we analyze the performance of four low-GWP alternative refrigerants (R32, R452B, R454B, and R466A) relative to the conventional R410A and draw conclusions on the relative performances for providing heating in cold climates based on the Air-Conditioning, Heating, and Refrigeration Institute (AHRI) 210/240 standard for two-speed heat pumps. The simulations are carried using the Department of Energy, Oak Ridge National Laboratory (DOE/ORNL) Heat Pump Design Model (HPDM), a well-known heating, ventilation, and air conditioning (HVAC) modeling and design tool in the public domain and the HVAC research and development community. The results of the simulation are further scrutinized using exergy analysis to identify sources of systemic inefficiency, the root cause of lost work. This rigorous approach provides an exhaustive analysis of alternate low-GWP refrigerants to replace R410A using available compressors and system components, without compromising performance.