Salinity, a severe worldwide issue, compromises the economic production of medicinal plants including mints and causes drug-yield decline. γ-Aminobutyric acid (GABA) is a tolerance-inducing signaling bio-molecule in various plant physiological processes. Pineapple mint (Mentha suaveolens Ehrh.) is a valuable medicinal herb with an exhilarating scent of citrus fruit. Piperitenone oxide is the major bioactive constituent of its essential oil, having signifcant demand by pharmaceutical industries. Nonetheless, modeling and optimizing the efective concentration of GABA remain within twin foci of interest. Therefore, a two factor-fve level (NaCl 0-150 mM and GABA 0-2.4 mM) central composite design was conducted to model and optimize drug yield and physiological responses of M. suaveolens. Based on the design of experiments (DoE) approach, diferent linear, quadratic, cubic, and quartic models were assigned to the response variables. Change trends of shoot and root dry weights followed a simple linear model, whereas sophisticated models (i.e., multiple polynomial regression) were ftted to the other traits. NaCl stress inevitably reduced root and shoot dry weight, piperitenone oxide content, relative water content, pigments content, and maximum quantum yield of PSII. However, content of malondialdehyde (MDA) and total favonoid, and DPPH radical scavenging activity were increased under salinity. Under severe NaCl stress (150 mM), the essential oil content (0.53%) was increased three times in comparison with control (0.18%). Optimization analysis demonstrated that the highest amount of essential oil (0.6%) and piperitenone oxide (81%) as a drug yield-determining component would be achievable by application of 0.1–0.2 mM GABA under 100 mM NaCl. The highest dry weight of root and shoot was predicted to be achieved at 2.4 mM GABA. Overall, extremely severe NaCl stress (i.e., more than 100 mM) in which a sharp drop in yield components value was observed seemed to be out of M. sua
