Soil salinity is one of the main abiotic stresses affecting yield in major crop plants, including legumes. Research carried out on model legumes such as barrel medic (Medicago truncatula Gaertn.) showed that the Tyrosyl-DNA phosphodiesterase 2 (MtTdp2) DNA repair gene, involved in the removal of topoisomerase-DNA covalent complexes, play a key role in the plant response to osmotic and copper stresses. However, no informations are currently available about the involvement of MtTdp2 in response to salt stress and salt shock. In the present study we investigated the role of MtTdp2 under salinity (0, 50, 100, 150 and 200 mM NaCl) stress conditions in transgenic M. truncatula overexpressing the MtTdp2 gene. The level of salt tolerance of Tdp2-28 selected transgenic line was significantly higher than control as measured by the increase in shoot fresh weight, shoot dry weight and salt sensitivity index, in response to 100mM NaCl. After salt stress, Tdp2-28 transgenic line showed significantly higher chlorophyll and carotenoid total contents, 2,2-Diphenyl-1-Picrylhydrazyl radical scavenging activity, and significantly lower levels of oxidative DNA damage than the control line. Interestingly, the expression levels of several genes, including genes linked to genome maintenance and regulation of DNA topology (MtTdp1, MtTop2), base excision repair pathway (MtOGG1) and double strand break sensing/repair (MtMRE11) were enhanced in Tdp2-28 transgenic shoots under salt stress conditions as compared to their controls. These findings suggest that MtTdp2 play an important role in plant tolerance to salt stress. Key messageOverexpression of MtTdp2 gene in Medicago truncatula confers salt stress tolerance through better plant growth performances, higher chlorophyll and carotenoid contents, increased antioxidant capacity, reduced oxidative DNA damage, and by up-regulation of several genes involved in DNA metabolism.