Objective To analyze the changes in serum levels of periostin (POSTN), pentraxin-3 (PTX3), and soluble fms-like tyrosine kinase receptor 1 (sFlt-1) in children with Henoch-Schönlein purpura nephritis (HSPN) and their clinical significance. Methods A total of 77 pediatric patients diagnosed with HSPN and admitted to the Jinshui District General Hospital, Zhengzhou City, from October 2021 to February 2024 were enrolled as the study group, while another 77 healthy individuals undergoing physical examinations during the same period served as the control group. At admission, serum levels of POSTN, PTX3, and sFlt-1, along with urinary microalbumin, creatinine, and urea nitrogen, were compared between the two groups to analyze their correlations. Additionally, the serum marker levels were compared among patients stratified by different pathological grades and clinical outcomes at admission, and their predictive value for clinical outcomes was investigated. Results The levels of serum POSTN, PTX3, sFlt-1, along with urinary microalbumin, creatinine, and urea nitrogen at admission in the study group were significantly higher than those in the control group (P<0.05). The serum levels of POSTN, PTX3, and sFlt-1 at admission in patients were positively correlated with renal function, urinary microalbumin, creatinine, and blood urea nitrogen (P<0.05). The serum levels of POSTN, PTX3 and sFlt-1 at admission in children with nephritis grade I-III were significantly lower than those in children with nephritis grade Ⅳ-Ⅵ (P<0.05); compared with the children with treatment failure, the serum levels of POSTN, PTX3 and sFlt-1 at admission in the effective children were significantly lower (P<0.05); the AUCs for predicting treatment failure based on serum POSTN, PTX3, sFlt-1 levels individually and jointly at admission were 0.837, 0.828, 0.832, and 0.935, respectively. Conclusion Serum POSTN, PTX3, and sFlt-1 play a role in the onset and progression of HSPN and are correlated with the renal pathological conditions in children with HSPN. These markers can effectively indicate the clinical therapeutic efficacy in children and hold significant value in predicting treatment outcomes.