Soil salinity and bicarbonate-induced alkalinity severely limit melon productivity by disrupting physiological and biochemical processes. This study evaluated the effectiveness of grafting an Iranian cantaloupe cultivar, ‘Til-e-Sabz’, onto Cucurbita maxima × C. moschata rootstock in mitigating salinity (10 mM NaCl; 2.7 dS m−1) and alkalinity (10 mM NaHCO3; 2.6 dS m−1) stress in soilless culture. Compared to non-grafted plants, grafted plants exhibited 22–35% greater leaf area, 28–40% higher shoot and root fresh biomass, and 25–38% higher dry biomass under both stress conditions. Relative chlorophyll content (SPAD) and total chlorophyll were reduced by stress but remained 15–21% higher in grafted plants. Carotenoid content was also maintained at 10–14% higher levels in grafted plants compared to non-grafted controls. Proline and soluble protein accumulation increased significantly under stress, with grafted plants accumulating 18–25% more proline and 12–20% more protein, indicating enhanced osmotic adjustment. Sodium levels increased in the roots and shoots under stress. However, grafted plants maintained 30–45% lower Na accumulation relative to non-grafted plants. In contrast, grafted plants showed up to 27% higher phosphorus and 32% higher iron uptake, while maintaining greater potassium retention (18–24%) under both salinity and alkalinity. Overall, grafting significantly improved physiological resilience and ion homeostasis, leading to enhanced stress tolerance. These findings demonstrate that grafting is a promising agronomic strategy to sustain melon production in saline and alkaline environments associated with increasing soil and water degradation.