Immunoglobulin A nephropathy (IgAN) is an autoimmune kidney disease with complex pathogenesis leading to end-stage renal damage. The crucial pathological characteristic in IgAN is IgA immune complexes deposition accompany with mesangial cell proliferation and mesangial matrix expansion. Artemisinin (ART) is isolated from traditional Chinese medicine Artemisia annua L. Hydroxychloroquine (HCQ) is a classical antimalarial drug used to treat autoimmune diseases. Both of them possess immunosuppressive, immunomodulatory and anti-inflammatory features. The aim of this study was to investigate the pharmacological effects of ART combined with HCQ (AH) and explore the underlying mechanisms in IgAN. In vivo, our results showed that All could significantly improve kidney dysfunction, decrease mesangial matrix expansion as well as immune complexes in mesangial area visualized by H&E and PAS staining. The depositions of IgA immune complexes and complement 3 (C3) were obviously reduced after AH treatment by immunofluorescence. Interestingly, the morphology of kidney and spleen was significantly swelled but reverted by AH in IgAN rats. Further mechanistic study showed that the higher proportions of the Th2 and Th17 cells were reduced but the lower differentiation of Th1 and Treg cells subsets were promoted by AH. Taken together, this study demonstrated that there was an immunosuppressive effect of AH therapy on IgAN rats via regulating the differentiation of CD4 + T cell subsets, which provided an alternative approach for IgAN treatment.