Cold atmospheric plasma generates reactive oxygen and nitrogen species (RONS) that dissolve in water, forming plasma-activated water (PAW) and inducing complex chemical changes and biological responses. PAW, enriched with nitrogen (N) species, emerges as a sustainable alternative to fertilisers by combining signalling (ROS) and N supplementation (RNS). This study aims to investigate the dual role of PAW in lettuce, Lactuca sativa (cv. Matilda), grown under either N-sufficient or N-deprived half-strength Hoagland solutions. Four treatments were evaluated: control, seed priming in PAW-activated Hoagland, PAW-activated Hoagland cultivation, and the combination of the latter two, under both N-content regimes.Under N-sufficient conditions, seed priming in PAW increased the lettuce head fresh weight up to 40%, chlorophyll a+b by 25%, and the sensory scores (freshness, juiciness), compared to the control. Under N-deprived conditions, PAW partially compensated for N-deficiency, increased the plant growth up to 50%, photosynthetic pigments and quercetin (up to 20%), and antioxidant enzymes (e.g., APX and G-POX increased up to 2x). Principal component analysis confirmed N-content as the primary variance driver (PC1 69—71%), with PAW modulating redox homeostasis tissue-specificity.Our results demonstrate the capacity of PAW to enhance plant growth, metabolism, and quality, even in N-deprived conditions, to address gaps in plasma agriculture by highlighting the PAW nutritional and signalling contributions. PAW thus represents a promising, eco-friendly strategy.