Suppressor of cytokine signaling 3 (SOCS3) has been characterized as one of the most crucial negative regulator in the JAK2/STAT3 signaling pathway. However, there are few studies on the relationship between SOCS3 and pediatric acute lymphoblastic leukemia (ALL). This study analyzes the influence of SOCS3 expression on the risk and the progression of pediatric ALL and the underlying mechanism. The levels of SOCS3, p-JAK2, p-STAT3, SOCS3 methylation, CD4+CD25+CD127lowTreg were detected by PCR, laser confocal microscopy, western blot, bisulfite sequencing and flow cytometry at different progression of ALL. We found that the SOCS3 expression level at initial diagnosis (DG) of ALL patients was significantly lower than that of healthy controls (HC), while the expression of SOCS3 methylation was opposite. The expression of SOCS3 and SOCS3 methylation were returned to normal in the complete remission (CR) stage, and there were no difference between resistance, relapse and initial diagnosis. The expression of SOCS3 decreased and weakened the inhibition of pSTAT3 expression in DG, resistance and relapse groups. The levels of Treg cells in ALL children were significantly higher than those in the HC children. There was a positive correlation between the expression level of STAT3 and the expression level of Treg cells in children with ALL, while that was negatively correlated with the expression levels of Treg cells. Compared with high-level of SOCS3, the low-level of SOCS3 patients had more high risk factors, as higher WBC counts, LDH level and much more poor prognostic genes. SOCS3 methylation leads to low-expression of SOCS3, which can lead to continuous activation of JAK/STAT3 and increased expression of Treg cells, which in turn affects the anti-tumor immunological effect of the body. Taken together, our data show that monitoring the level of SOCS3 can contribute to the understanding of the state of illness and evaluate the risk of progression of ALL.