Simplified soilless cultivation (SSC) systems have globally spread as growing solutions for low fertility soil regions, low availability of water irrigation, small areas and polluted environments. In the present study, four independent experiments were conducted for assessing the applicability of SSC in the northeast of Brazil (NE-Brazil) and the central dry zone of Myanmar (CDZ-Myanmar). In the first two experiments, the potentiality for lettuce crop production and water use efficiency (WUE) in an SSC system compared to traditional on-soil cultivation was addressed. Then, the definition of how main crop features (cultivar, nutrient solution concentration, system orientation and crop position) within the SSC system affect productivity was evidenced. The adoption of SSC improved yield (+35% and +72%, in NE-Brazil and CDZ-Myanmar) and WUE (7.7 and 2.7 times higher, in NE-Brazil and CDZ-Myanmar) as compared to traditional on-soil cultivation. In NE-Brazil, an eastern orientation of the system enabled achievement of higher yield for some selected lettuce cultivars. Furthermore, in both the considered contexts, a lower concentration of the nutrient solution (1.2 vs. 1.8 dS m−1) and an upper plant position within the SSC system enabled achievement of higher yield and WUE. The experiments validate the applicability of SSC technologies for lettuce cultivation in tropical areas.