Furrow sowing could significantly decrease salt damage to wheat; however, the molecular mechanism in wheat is not well known. In this study, a split-root system was used to simulate non-uniform root zone salinity. Our hydroponic experiments showed that wheat seedlings under non-uniform salt stress probably use a salt avoidance strategy to ensure growth. RNA sequencing analysis showed that 1648 and 3245 differentially expressed genes were identified in 0/150 and 75/75 salt treatments, respectively, with an intersection of 690 genes. Gene ontology terms representing normal growth were specifically enriched by upregulated genes in the 0/150 treatment and downregulated genes in the 75/75 treatment, and terms representing phytoremediation were specifically enriched by upregulated genes in the 75/75 treatment and downregulated genes in the 0/150 treatment. Differentially expressed genes that are probably associated with salt stress and transcription factors showed significantly higher expression in the 75/75 treatment than in the 0/150 treatment. These findings suggest that a uniform salt treatment causes wheat to initiate a more complex salt tolerance mechanism for salt stress. In addition, the expression of 11 genes annotated as peroxidase was higher in the 0/150 treatment than in the 75/75 treatment, and the enzyme activity showed the same trend, indicating that peroxidase probably played a role in the better performance of wheat plants under non-uniform salt stress. Pot culture experiments showed that wheat plants under non-uniform salt stress produced higher yields than those under uniform stress, further indicating that inducing unequal salt distribution in soil could significantly improve wheat cultivation.