Salinity restricts seed germination and seedling growth through induction of osmotic and oxidative stresses. Therefore, this study aimed to enhance salinity tolerance in quinoa seed by pre-optimized osmo-priming treatments of CaCl2 (10 mM, 10 °C, 10 h) and KNO3 (150 mM, 5 °C, 24 h). The results showed that these treatments developed the cellular defense mechanisms in seeds as ‘priming memory’ that could improve the physiological and biochemical responses to salinity in post-priming stages. The germination capacity and seedling growth decreased with increasing salinity that was accompanied with a higher content of MDA and H2O2. However, the improvement of primed seed vigor against high salinity was explained by increasing the biological defense mechanisms including antioxidant enzymes (CAT, APX, SOD, GPX and PPO) and antioxidant metabolites (DPPH antioxidant activity, phenolics, flavonoids, ascorbic acid), particularly in presence of salt stress. In addition, Ca2+ and K+ priming acquired salinity tolerance in post-priming stages through a significant increase in the accumulation of proline, glycine-betaine, soluble carbohydrate. Improvement in homeostasis of K+/Na+ ratio by promoting K+ maintenance and Na+ exclusion was also found in post-priming stages. These observations may be utilized as effective methods in improving salinity tolerance of quinoa seed germination in saline agriculture by improving the antioxidant system, osmolyte accumulation and mineral nutrient homeostasis.