In year-round hot climatic conditions, conventional air conditioning systems consume significant amounts of electricity primarily generated by conventional power plants. A compression-assisted, multi-ejector space cooling system driven by low-grade solar thermal energy is investigated in terms of energy and exergy performance, using a real gas property-based ejector model for a 36 kW-scale air conditioning application, exposed to annually high outdoor temperatures (i.e., up to 42 °C), for four working fluids (R11, R141b, R245fa, R600a). Using R245fa, the multi-ejector system effectively triples the operating condenser temperature range of a single ejector system to cover the range of annual outdoor conditions, while compression boosting reduces the generator heat input requirement and improves the overall refrigeration coefficient of performance (COP) by factors of ~3–8 at medium- to high-bound condenser temperatures, relative to simple ejector cycles. The system solar fraction varies from ~0.2 to 0.9 in summer and winter, respectively, with annual average mechanical and overall COPs of 24.5 and 0.21, respectively. Exergy destruction primarily takes place in the ejector assembly, but ejector exergy efficiency improves with compression boosting. The system could reduce annual electric cooling loads by over 40% compared with a conventional local split air conditioner, with corresponding savings in electricity expenditure and GHG emissions.