High-temperature heat pumps consist of a promising choice for substituting conventional boilers and producing hot water with temperature levels in the range of 70–80 °C. The use of high-temperature heat pumps makes it possible to exploit the existing radiators in existing buildings to achieve effective heating of the indoor space and keep thermal comfort at high standards. The goal of this work is the detailed investigation of a high-temperature heat pump, with the R1234ze(E) as the working medium for producing heating at 80 °C for space-heating purposes, in Greek climate conditions. The analysis was conducted at two locations, one in the south (Athens—Zone B) and one in the north (Thessaloniki—Zone C), in order to examine the performance of the study’s technology in the most representative locations of Greece. The thermodynamic analysis of the heat pump was performed with a developed model in Engineering Equation Solver by exploiting real data from the compressor manufacturer and by practically using a gray box model. The heating thermal loads were calculated with a dynamic analysis using TRNSYS software. According to the final results, the high-temperature heat pump was beneficial when compared to a conventional oil boiler from energy, financial, and environmental points of view. The net savings were found at EUR 6448 for Athens and EUR 13,161 for Thessaloniki; the simple payback period resulted in 8.03 years for Athens and 6.11 years for Thessaloniki, while the CO2 emissions avoidance was found at 35% for Athens and 32% for Thessaloniki. Last but not least, the lifetime CO2 emissions reduction was calculated at 20,882 kgCO2 for Athens and 35,278 kgCO2 for Thessaloniki.