Overall, there are numerous sustainable sources of renewable, low-temperature heat, principally solar energy, geothermal energy, and energy produced from industrial wastes. Extended utilization of these low-temperature alternatives has a certain capacity of decreasing fossil fuel use with its associated very hazardous greenhouse gas emissions. Researchers have commonly recognized the organic Rankine cycle (ORC) as a feasible and suitable system to produce electrical power from renewable sources based on its advantageous use of volatile organic fluids as working fluids (WFs). Researchers have similarly shown an affinity to the exploitation of zeotropic mixtures as ORC WFs due to their capability to enhance the thermodynamic performance of ORC systems, an achievement supported by improved fits of the temperature profiles of the WF and the heat source/sink. This paper determines both the technical feasibility and the benefits of using zeotropic mixtures as WFs by means of a simulation study of an ORC system. This study analyzes the thermodynamic performance of ORC systems using zeotropic WF mixtures to produce electricity driven by low-temperature solar heat sources for use in buildings. A thermodynamic model is created with an ORC system with and without a regenerator. Five zeotropic mixtures with diverse compositions between 0 and 1 in 0.2 increments of R245fa/propane, R245fa/hexane, R245fa/heptane, pentane/hexane, and isopentane/hexane are assessed and compared with identify the best blends of mixtures that are able to produce superior efficiency in their system cycles. Results disclosed that R245fa/propane (0.4/0.6) with regenerator produces the highest net power output of 7.9 kW and cycle efficiency of 9.4% at the operating condition with a hot source temperature of 85 °C. The study also investigates the effects of the volume flow ratio, and evaporation and condensation temperature glide on the ORC’s thermodynamic performance. Following a thorough analysis of each mixture, R245fa/propane is chosen for a parametric study to examine the effects of operating factors on the system’s efficiency and sustainability index. It was found that the highest cycle efficiency and highest second law cycle efficiency of around 10.5% and 84.0%, respectively, were attained with a mass composition of 0.6/0.4 at the hot source temperature of 95 °C and cold source temperature of 20 °C with a net power output of 9.6 kW. Moreover, results revealed that for zeotropic mixtures, there is an optimal composition range within which binary mixtures are tending to work more efficiently than the component pure fluids. In addition, a significant increase in cycle efficiency can be achieved with a regenerative ORC, with cycle efficiency in the range 3.1–9.8% versus 8.6–17.4% for ORC both without and with regeneration, respectively. In conclusion, utilizing zeotropic mixtures may well expand the restriction faced in choosing WFs for solar-powered ORC-based micro-combined heat and power (CHP) systems.