Henoch-Sch€ onlein purpura nephritis has become a significant threat to children's health. Traditional combined therapy of glucocorticoids and cyclophosphamide leads to severe toxicity and complications. Therefore, identifying a feasible and effective strategy with low side-effects for the treatment of Henoch-Sch€ onlein purpura nephritis is of great significance. Methods: A randomized, controlled trial was carried out. A total of 279 children with Henoch-Sch€ onlein purpura nephritis were recruited and randomly divided into three groups: control group (receiving the current standard therapy), TA group (receiving tacrolimus) and TA + tripterygium glycosides group (receiving tacrolimus + tripterygium treatment). The total duration of the trial was 6 months, and the duration of follow-up observation was 9 months. Results: Various therapies showed similar therapeutic effects in the third and sixth months. The relief of Henoch-Sch€ onlein purpura nephritis symptoms caused by TA + tripterygium glycosides was slower than the TA and control groups. The incidence of adverse reactions in the TA + tripterygium glycosides group was lower in the control and TA groups. The final treatment effect of the experimental groups was better than the control group. The recurrence rate in the TA + tripterygium glycosides group was also significantly lower. Conclusion: Tacrolimus and tripterygium glycosides combined therapy had better effects and safety for long-term treatment of Henoch-Sch€ onlein purpura nephritis.