Among water-based mitigation strategies against urban overheating, dry mist systems are especially promising, given their local impact, cost-effectiveness and controllability. Intense cooling capacity has been reported under a variety of climates, however, there is a growing need to define specific design guidelines towards an informed and optimized use of the technology. Parametric analysis on validated models would assist in determining type and degree of correlation between key parameters, as well as magnitude and predictability of the cooling capacity. In this paper, for the first time, a 3D microclimatic model in ENVI-met is used to simulate a misting system installed in Rome, Italy, with high prediction accuracy for the air temperature (R2≃0.87, RMSE≃0.84 °C). The calibrated ENVI-met model is used then to perform parameterizations on the water mist system, focused on the role of three key design variables: i) water flow rate, ii) injection height and iii) local wind speed. Results show that the most significant thermal drops tend to occur close but out of the misted perimeter following the wind direction, with cooling effects further stretched for tens of meters. The cooling capacity increases with the total water flow rate (+0.2 °C per 10 l/h increment) and in presence of calm air (+35–40% per 0.8 m/s deceleration). Lower injections intensify the cooling a pedestrian height, which could be especially beneficial under windy conditions. Further research would target climate dependencies to extend the applicability of the above results and build up cohesive guidelines at the hands of urban planners and practitioners.