Sustainable agriculture necessitates innovative solutions to enhance plant growth while optimizing resource efficiency. Plasma discharge generates reactive oxygen and nitrogen species (NH4+, NO3−, and NO2−), which form plasma-activated water upon dissolution, affecting the nutritional solution pH and electrical conductivity (EC) and, consequently, plant development. Four treatments were applied, resulting from combining high or low plasma discharge intensities at 45 or 60 min spray intervals: low plasma discharge with a 45 min interval (T1), low plasma discharge with a 60 min interval (T2), high plasma discharge with a 45 min interval (T3), and high plasma discharge with a 60 min interval (T4). The experiment followed a 4 × 5 × 2 factorial design comprising the four treatments, five replications per treatment, and two independent experimental repeats, resulting in forty experimental units. Each unit contained 12 lettuce plants, for a total of 480 plants. The multivariate analysis of variance confirmed statistically significant treatment effects. The combination of high plasma intensity and a 45 min spray interval significantly increased the growth parameters and yield as compared with the other treatments. In particular, compared with T1, which produced the lowest values across all measured parameters, T3 resulted in a 97% increase in leaf area, a 72% increase in stem diameter, a 49% increase in leaf number, a 44% increase in leaf width, and a 30% increase in leaf length. Additionally, T3 increased edible yield by 210% and total biomass production by 203% compared with T1. These results demonstrate the combined effect of plasma intensity and spraying frequency in optimizing plant development in aeroponic systems. As far as mineral uptake is concerned, T3 increased the nitrogen, potassium, phosphorus, calcium, and magnesium concentrations by 18.2%, 16.7%, 32.3%, 20.2%, and 11.2%, respectively, compared with T1. The regression analysis further validated the robustness of the findings, indicating plasma intensity to be a dominant factor. Enhanced mineral uptake (N, P, K, Ca, and Mg) and consistent growth trends across treatments highlighted the significance of plasma technology in optimizing plant growth, yield, and nutrient absorption, suggesting it is a sustainable and efficient approach to modern agriculture.