The impact of salt stress is becoming more prevalent each year, largely due to the effects of climate change. Limited availability of salt-free water is rising concern for hydroponics lettuce production. Despite evidence supporting salt stress-induced quality losses and physiological changes, studies on romaine lettuce salt-stress tolerance are limited. This study examined the mechanism underlying the sodium chloride (NaCl) tolerance (0, 50, 100, and 150 mM) of lettuce on its growth and nutrition at late-rosette and early head-formation stages. Results revealed 76% fresh mass reduction under increased NaCl at both stages. The study also found unchanged carbon assimilation with reduced stomatal conductance under increased NaCl. Salt-stressed lettuce accumulated more boron and iron but had reduced phosphorus and calcium. Phenolics and sugars increased linearly under salt stress, suggesting that lettuce responds to increased oxidative stress at both stages. A positive association between salt treatment and sodium to potassium ion ratio indicated lettuce sensitivity to salt stress at both stages.