Two experiments were conducted in different cropping seasons under Mediterranean climatic conditions to investigate the impact of two cooling systems (fan-pad evaporative as opposed to fan ventilation) on greenhouse microclimate and soilless cucumber growth. The second objective of the experiment was to determine the most appropriate irrigation regime (between 0.24 and 0.32 L m−2) in relation to crop water uptake and greenhouse fertigation effluents. The use of a fan ventilation system enhanced the vapor pressure deficit; thus, the crop transpiration improved by 60% in relation to the transpiration rates of plants grown under the fan-pad system. Higher transpiration rates alleviated the heat load as the external–inside greenhouse air differences declined from 6.2 °C to 3 °C. The leaf–air temperature differential indicated that plants were not facing any water stress conditions for both cooling systems tested; however, fan ventilation reduced drainage emissions outflows (95% decrease) compared with evaporative cooling. Results also demonstrated that an irrigation regime of 0.24 L m−2 can be applied successfully in soilless cucumber crops, keeping the drainage to a minimum (20% of the nutrient solution supply). These results suggest that fan ventilation cooling system in conjugation with an appropriate irrigation regime prevents overheating and minimizes the nutrient and water losses in spring-grown soilless cucumber crops in Mediterranean greenhouses without compromising yield