High Temperature Heat Pumps (HTHPs) are increasingly recognized as a key technology for decarbonizing industrial heating processes. This study presents a comprehensive thermodynamic and exergy analysis of various Low-GWP Refrigerants used in HTHP systems operating under different temperature lifts and condensation temperatures. The refrigerants evaluated include R718 (water), R600 (butane), R123, R1234ze(Z), R1233zd(E), R1224yd(Z), and R245fa. Results show that R718 consistently outperforms other refrigerants in terms of COP and exergy efficiency. At a temperature lift of 40 ◦ C and a condensation temperature of 150 ◦ C, R718 achieves a COP of 6.9 and an exergy efficiency of 49%. Even at an 80 ◦ C lift, its COP remains at 3.0, with exergy efficiency rising to 55%, indicating strong thermodynamic resilience. However, R718 also exhibited the highest discharge temperatures, requiring larger compressors and advanced system configuration. In contrast, R600 exhibits the lowest COP and highest exergy destruction, making it unsuitable for high-lift applications. Exergy destruction analysis identified the compressor as the dominant source of irreversibility, contributing more than 50% of total exergy destruction under all conditions. Total exergy destruction increased sharply with higher temperature lifts, ranging from 5 to 12% at 40 ◦ C to 10–30% at 80 ◦ C. Component-level analysis highlighted that improvements in compressor design and refrigerant selection are critical to minimizing system losses. Notably, R1233zd(E) and R1234ze(Z) showed lower compressor and condenser irreversibilities compared to other synthetic refrigerants. These results provide valuable guidance for refrigerant selection and system optimization in the development of efficient and sustainable HTHP technologies.