<p>Salinity is one of the most challenging environmental factors limiting plant development and yield by interfering with key physiological and metabolic activities. In this study, we explored how applying spermine externally could help <i>Plantago major L.</i> cope with salt stress. A detailed analysis was carried out, examining changes in plant growth, water balance, biochemical composition, enzyme activity, gene expression, and metabolite accumulation. Plants were grown under four different conditions: untreated control, salinity stress alone, spermine treatment alone, and salinity combined with spermine. Exposure to salt significantly hindered shoot and root growth, decreased chlorophyll levels and water retention, and increased oxidative stress and the buildup of certain stress-related compounds. However, the addition of spermine, especially in the combined salinity and spermine treatment, helped alleviate these negative effects. It improved water content, preserved chlorophyll, lowered damage markers like malondialdehyde, and boosted the plant’s antioxidant system. On a molecular level, genes such as phenylalanine ammonia-lyase (<i>PAL</i>), caffeic acid O-methyltransferase (<i>COMT</i>), and 3-deoxy-D-arabino-heptulosonate-7-phosphate synthase (<i>DAHPS</i>)—involved in the production of protective secondary metabolites—showed altered expression patterns in response to stress and spermine. These changes were mirrored in the increased levels of compounds like phenylalanine, caffeic acid, and rosmarinic acid. Statistical analyses, including principal component analysis and clustering, highlighted the salinity plus spermine group as having the most favorable overall response. Together, the results suggest that spermine strengthens <i>Plantago major</i>’s ability to withstand salinity by triggering a broad range of protective mechanisms and may serve as a valuable tool for improving plant resilience in salt-affected soils.</p>