Purpose <p>The aims of the present study are to examine how lettuce plants (<i>Lactuca sativa L.</i>) responded to salinity stress in relation to four treatment groups: exogenous zinc oxide nanoparticles (ZnO-NPs) group, control group, sodium chloride (NaCl) group, and sodium chloride + exogenous zinc oxide nanoparticles (NaCl + ZnO-NPs group).</p> Methods <p>Cos Lettuce (Thai – MGS1376) was utilized as the experimental material. Four different treatments, such as zinc oxide (ZnO), exogenous zinc oxide nanoparticles (ZnO-NPs), NaCl, and sodium chloride + exogenous zinc oxide nanoparticles (NaCl + ZnO nanoparticles) were used.</p> Results <p>The findings revealed that exogenous ZnO-NPs might increase growth and biomass of plants in salinity-stressed environments. After applying various ZnO-NPs, lettuce leaves potassium ion (K⁺) concentration and potassium to sodium ion (K⁺/Na⁺) ratio increased. Significant changes were found in proline content, malondialdehyde (MDA) content, and superoxide anion (O₂⁻) generation between ZnO-NPs and control groups (<i>p</i> ≤ 0.05). There were no significant differences between the ZnO-NPs and control groups in terms of soluble sugar content, superoxide radical production rate, hydrogen peroxide (H₂O₂) content, or ascorbic acid content, implying that oxidative damage to the leaves was reduced. ZnO-NPs enhanced shoot and root dry weight, fresh weight, and leaf area, alongside increased chlorophyll levels.</p> Conclusion <p>The findings are implying ZnO-NPs’ potential for boosting lettuce growth in saline conditions. The ZnO nanoparticles can be a helpful ecologically friendly treatment to improve plant tolerance and antioxidant activity, hence reducing salt stress-related damage.</p> Graphical Abstract <p></p>