Iodine, applied as iodate in biofortification programs (at doses of ≤80 μM), has been confirmed to improve the foliar biomass, antioxidant response, and accumulation of phenol compounds in lettuce plants. The changes in phenolic compounds induced by the iodate application appear to have functional consequences in the response of salt-stressed plants. Thus, the aim of the present study was to determine whether the application of iodate can improve the response of severe salinity stress and whether the resistance can be attributed to the phenolic metabolism in lettuce ( Lactuca sativa cv. Philipus), a glycophyte cultivated for food and consumed year round. In this work, the application of iodate, especially at 20 and 40 μM, in lettuce plants under salinity stress (100 mM NaCl) exerted a significantly positive effect on biomass and induced higher activity in the enzymes shikimate dehydrogenase and phenylalanine ammonia-lyase as well as the lower MW phenol-degrading enzyme polyphenol oxidase. This increased hydroxycinnamic acids and derivatives in addition to total phenols, which appear to act as protective compounds against salinity. This study reveals that in agricultural areas affected by this type of stress, the application of iodate may be an effective strategy, as it not only improves lettuce plant growth but also supplements the human diet with phenolic compounds and the trace element iodine.