Environmental stresses such as low soil moisture and soil nutrient deficiency are among the main causes of low crop productivity in arid and semi-arid regions. Soilless cultivation is intensively used in protected agriculture to improve control over the growing environment and avoid uncertainties in the soil's water and nutrient status, leading to better result in water use efficiency, while maintaining the quality of the yield. Therefore, this study was conducted at the Faculty of Agriculture, An Najah University, Palestine, during 2016–17 growing season to investigate the effects of three soilless culture systems compared to agricultural soil growing media on yield and water use efficiency of lettuce crop under greenhouse cultivation. Four different growing media were investigated; pure soil serves as a control, pure volcanic tuff (VT), peat moss perlite mixture (2:1 v/v) and the nutrient film technique (NFT) (hydroponic) and their effect on the growth and productivity of lettuce were monitored. Results showed no significant differences in lettuce crop fresh weight and total fresh weight produced per unit area (m2) within the different growing media tested. In contrast, the different growing media significantly influenced the water use efficiency (WUE) values. Peat moss-perlite mixture and the nutrient film technique (NFT) media resulted in the highest WUE and can save water remarkably, with an irrigated water saved ranging from 94 to 123%, respectively. Overall, results suggest that the NFT hydroponic system is the most efficient system for water-saving and water use efficiency.