Water limitation associated with climate changes leads to increased use of poor-quality water for irrigation, in turn enhancing soil salinization. Soil salinity has become a major threat in many regions of the world, limiting plant growth and productivity. The development of alternative salt-tolerant rootstocks that can also withstand biotic stresses is a priority for the citrus industry. Polyploidy is one of the major forces driving plant evolution and provides great advantages in coping with environmental constraints. Tetraploidy has been shown to enhance plant adaptation to various abiotic stresses, including salt stress. The evaluation of allotetraploid citrus hybrids, which can combine desired traits from both parents, appears to be an effective way to address the rootstock challenge. Cleopatra mandarin (Citrus reshni Hort. Ex Tan.) (CL), a well-known citrus rootstock, displays good tolerance to cold, drought, chlorides, and limestone. However, it is susceptible to tristeza, exocortis, and phytophtora. On the contrary, Trifoliate orange (Poncirus trifoliata (L.) Raf.) (PO) is a salt-sensitive rootstock but is resistant to phytophtora and tristeza. The present study is the first to evaluate the salt stress response of a Citrandarin hybrid generated from a cross between Cleopatra and Poncirus at two ploidy levels: diploid (2x) and tetraploid (4x). To dissect the hybrid response, photosynthetic activity, antioxidant metabolism, mineral uptake, and transcriptomic regulation were studied in two tissues: leaves and roots. Using various multivariate approaches, the study successfully deciphered the complexity of the multilevel response of each 2x and 4x hybrid. Although ploidy level accounted for very limited differences between 2x and 4x, they both showed a high and common tolerance to stress. However, the 4x exhibited a higher level of tolerance than the 2x thanks to its specific leaf photosynthesis and root antioxidant metabolism. Finally, this study provides insights into the finely tuned mechanisms underlying the respective salt stress adaptation of the 2x and 4x Citrandarins thanks to the identification of key genes selected using covariance analysis.