The PADRE (Pathogen and abiotic stress response, cadmium tolerance, disordered region-containing) family of genes, which contains the structural DUF4228 domain of unknown function (DUF), has been reported to be associated with plant responses to abiotic stresses. However, the specific functions of this family in the salt stress response remain unknown. AtPADRE13 is induced by salt stress and ABA (abscisic acid). After the overexpression of AtPADRE13 in Arabidopsis, seeds were found to be insensitive to ABA treatment. After salt treatment, the overexpression lines presented a significantly lower survival rate, increased MDA (Malondialdehyde) content, and reduced antioxidant enzyme activities compared with the wild-type, and were more sensitive to salt stress. Transcriptome data analysis further revealed that AtPADRE13 overexpression resulted in different degrees of down-regulation for a series of positive regulators related to ABA catabolism, transport, and their mediated plant responses to salt stress. In addition, the expression of genes related to ROS (reactive oxygen species) scavenging was down-regulated. In conclusion, AtPADRE13 plays a negative regulatory role in the response to salt stress in Arabidopsis.