In a 2-year study, the morphophysiological and qualitative changes imposed to greenhouse lettuce (Lactuca sativa L.) by an increasing concentration of NaCl in the irrigation water were determined. Plants were grown under soil conditions and supplied with irrigation water having electrical conductivities (ECs) of 0.7 (control), 0.9, 1.8, 3.6, or 7.2 dS·m−1. Irrigation with saline water resulted in linear decrease in plant growth parameters (i.e., leaf number, total leaf area and head diameter), head fresh weight, and diameter as well as yield, especially at 1.8, 3.6, and 7.2 dS·m−1, confirming that lettuce is a salt-sensitive crop. The percentage of marketable yield reduction in comparison with nonsaline control treatment was 22.7%, 36.4%, 45.4%, and 63.6% at 0.9, 1.8, 3.6, and 7.2 dS·m−1, respectively. The reduction in marketable fresh yield has been partly compensated by a decrease in the nitrate content of salt-treated lettuce. The highest values of hydrophilic antioxidant activity were recorded in the nonsalinized treatment. The lowest values of lipophylic antioxidant activity (LAA) and total ascorbic acid were observed under severe stress conditions (7.2 dS·m−1). Net CO2 assimilation rate and leaf water potential (LWP) declined with increasing NaCl concentration in the irrigation water. Increasing salinity in the irrigation water induced a reduction in stomatal conductance (gs) as LWP dropped below −0.62 MPa.