A greenhouse experiment was conducted to evaluate the comparison of nutrient use efficiency, antioxidant assay, and nutritional quality of butter-head lettuce in five cultivation systems. For this experimental study, a split-boxes experimental arrangement in a completely randomized design (CRD) with three aeroponics systems (high pressure (T 1 ), low pressure (T 2 ), and ultrasonic nozzle (T 3 )), hydroponic system (T 4 ), and conventional cultivation system (T 5 ) was designed. The analyses of variance (ANOVA) were employed to assess yield, chlorophyll content, relative water content (RWC), nutrient use efficiency (NUE), 2,2-Diphenyl-1-picrylhydrazyl (DDPH), Hydrogen Peroxide (H 2 O 2 ), Ferric Reducing Antioxidant Power (FRAP), total phenolic (TPC), flavonoid content (TFC) and nutritional quality of butter-head lettuce. The experimental comparative results indicated that the shoot and root (fresh and dry) weight, root-to-shoot ratio, chlorophyll contents, CWC, NUE, DDPH, H 2 O 2 , FRAP, TPC, TFC, nitrate, vitamin C, and protein level were significantly (p<0.05) higher in T 2 treatment, and the values were significantly (p<0.05) lower in T 1 followed by T 5 treatment. Moreover, as mentioned earlier, the median values of the above-mentioned parameters were measured in aeroponics systems with low-pressure nozzle (T 3 ). It also found a strong positive correlation (r>0.7) among the Shoot (FW), Chlorophyll, RWC, NUE, and among TPC, TFC, DDPH, H 2 O 2 , and FRAP. This study demonstrates that butter-head lettuce grown in aeroponics systems with high-pressure nozzles may serve as a potential dietary source and is rich in natural antioxidants.