In the present study, the performance of a novel spray flash desalination system integrated with concentrated solar power is experimentally investigated and optimized. The effect of four factors, namely, flow rate (0.2–0.4 LPM), feed water temperature (30–50 °C), salinity (15,000–35,000 PPM), and vacuum pressure (0.1–0.5 bar), was examined on three responses (i.e., condenser exit temperature, boiler exit temperature, and distillate production). Mathematical models are developed for each response, and optimization is performed with Design Expert software using response surface methodology. The results revealed that the feed water temperature and vacuum pressure positively impacted condenser and boiler exit temperatures and vice versa for salinity and flow rate. However, the flow rate, feed water temperature, and vacuum pressure were found to impact the distillate production positively. The optimum factor settings are 0.4 LPM flow rate, 50 °C feed temperature, 15,000 PPM salinity, and 0.5 bar vacuum pressure for optimal condenser exit temperature of 55 °C, boiler exit temperature of 58.8 °C, and distillate 7010 mLPH. The energy and exergy analyses were conducted, and the mean efficiencies were found to be 55.6 % and 2.2 %, respectively.