【Objective】In arid and semi-arid regions, the coexistence of drought and high salinity imposes severe constraints on crop establishment, impairing seed germination and early seedling growth, consequently causing substantial agricultural losses. Seed priming with nanoparticles represents an emerging, economically viable, and environmentally sustainable approach to enhance crop performance under adverse conditions. Thus, harnessing this new approach in developing sustainable strategies to improve plant stress resilience is imperative.【Method】This study investigated the efficacy of cerium oxide nanoparticles (CeO2 NPs) as a seed priming agent in alleviating the detrimental effects of combined drought-salinity stress (simulated by 60 000 mg·L-1 polyethylene glycol (6% PEG-6000) and 50 mmolL-1 saline-alkali (NaCl：Na2SO4=9：4，pH adjusted by NaHCO3)) on alfalfa (Medicago sativa L.). Seeds were treated with CeO2NP suspensions (0, 1.0, 2.5, 5, 10, 15, and 20 mg·L-1) for 12 h and subsequently subjected to stress conditions for 14 d.【Result】The results demonstrated that drought-salinity stress significantly suppressed germination and seedling growth. However, priming with CeO2 NPs notably mitigated these inhibitory effects in a concentration-dependent manner, with the most pronounced improvements observed at 5 mg·L-1. At this optimal concentration, significant enhancements were recorded in germination potential, germination rate, germination index, vigor index, root length, shoot height, and fresh biomass compared to the non-primed stress group. Also, 5 mg·L?1 CeO2NP treatment also reduced membrane damage, as indicated by lower relative electrical conductivity (REC) and malondialdehyde (MDA) content, and decreased hydrogen peroxide (H2O2) accumulation under combined stress. Concurrently, it elevated the activities of antioxidant enzymes (catalase and ascorbate peroxidase) and the concentrations of osmoregulatory compounds (proline and soluble sugars). Correlation analysis revealed strong positive associations among growth parameters, which were negatively correlated with membrane injury indices. These findings suggest that CeO2 NP priming strengthens the synergistic interaction between the antioxidant system and osmotic adjustment, thereby preserving membrane integrity and promoting germination and seedling growth under combined stress. 【Conclusion】In conclusion, seed priming with 5 mg·L?1 CeO2 NPs effectively improves alfalfa establishment under drought-salinity stress conditions, offering a promising nano-agronomic strategy for sustainable crop production in marginal environments.