Heat waves and the related heat stress can increase human morbidity and mortality, decrease human productivity and increase building energy consumption for cooling. There is a need for sustainable systems to reduce heat stress in urban areas. Evaporative cooling by water spray systems is increasingly used for this purpose. However, the evaluation of the cooling potential of such systems is difficult. To our knowledge, a systematic investigation of the cooling potential of such a system in an actual urban area has not yet been performed. This paper presents high-resolution Computational Fluid Dynamics (CFD) simulations based on the 3D unsteady Reynolds-Averaged Navier-Stokes equations to assess the cooling potential by a water spray system with 15 hollow-cone nozzles. The system is numerically implemented for a courtyard in the Bergpolder Zuid region of Rotterdam, the Netherlands and operated during the heat wave period of July 2006. The simulations are validated based on wind-tunnel measurements of an evaporative cooling process and satellite imagery data during the heat wave period. The Universal Thermal Climate Index (UTCI) is used to assess the heat stress reduction due to evaporative cooling. The results show that for given values of injected water flow rate (ṁ w = 9.0 l/min) and height of the spray system (H = 3 m), a maximum temperature reduction and UTCI reduction of about 7 and 5 °C are achieved at pedestrian height. In addition, a thermal comfort improvement from strong heat stress (without spray system) to moderate heat stress up to a distance of 5 m from the spray line is obtained.