Salt stress is one of the abiotic stresses affecting crop growth and yield. The functional screening and mechanism investigation of the genes in response to salt stress are essential for the development of salt-tolerant crops. Here, we found that OXIDATIVE STRESS 2 (OXS2) was a salinity-induced gene, and the mutant oxs2-1 was hypersensitive to salt stress during seed germination and root elongation processes. In the absence of stress, OXS2 was predominantly localized in the cytoplasm; when the plants were treated with salt, OXS2 entered the nuclear. Further RNA-seq analysis and qPCR identification showed that, in the presence of salt stress, a large number of differentially expressed genes (DEGs) were activated, which contain BOXS2 motifs previously identified as the binding element for AtOXS2. Further ChIP analysis revealed that, under salt stress, OXS2 associated with CA1 and Araport11 directly through binding the BOXS2 containing fragments in the promoter regions. In conclusion, our results indicate that OXS2 is required for salt tolerance in Arabidopsis mainly through associating with the downstream CA1 and Araport11 directly.