Salinity poses a major threat to global agriculture, affecting over 20% of cultivated land and hindering the goal of increasing food production by 70% by 2050. Salt stress, primarily driven by Na+ accumulation, disrupts plant’s ion balance, leading to nutrient deficiency, oxidative stress, and reduced crop productivity. Halophytes, such as Sesuvium portulacastrum, offer a model for studying salt tolerance mechanisms due to their ability to thrive in high-salinity environments. The research on S. portulacastrum focuses on its growth modulation, ion homeostasis, physiological alterations, and metabolomic and proteomic responses under salinity stress. Sesuvium portulacastrum accumulates Na+ predominantly in its leaves and stems, with roots showing much lower levels, indicating efficient salt ion sequestration. Proteomic analysis revealed differential protein expression under NaCl and NaNO3 treatments, with key proteins involved in photosynthesis, carbohydrate metabolism, and stress response being significantly altered. Specifically, ATPase activity varied between the initial and adaptive stress stages, highlighting the plant’s dynamic response to salinity. Chloroplast proteins were notably affected, with increased expression of proteins like CAB8, CP26, and FeSOD under salt stress, correlating with enhanced photosynthetic efficiency and stress resilience. Metabolomic studies identified significant changes in metabolites such as sucrose, pinitol, and p-coumaryl alcohol, underscoring their roles in osmotic adjustment and oxidative damage mitigation. These comprehensive insights into the physiological, proteomic, and metabolomic responses of S. portulacastrum to salinity stress enhance our understanding of plant adaptation mechanisms and offer potential strategies for improving crop resilience in saline environments.