Systemic lupus erythematosus (SLE) is a chronic disease of the autoimmune system with multiple damages, most commonly renal damage. The aim of the present study is to examine the therapeutic ability of Qihuang Jianpi Zishen decoction (QJZ) on MRL/lpr mice and uncover its mechanism preliminarily. Twenty-four female MRL/lpr mice were assigned into the model, prednisolone, mycophenolate mofetil and QJZ groups randomly. Six C57BL/6 mice were considered as controls. Each group was treated with corresponding drugs for 4 weeks, anti-dsDNA autoantibodies, C3 and C4, renal function and renal histopathological changes were observed. The expression of GAS5/miR-21/sprouty1 axis and ERK/CREB pathway in kidney was identified by western blotting and qRT-PCR. Compared with MRL/lpr mice, anti-dsDNA autoantibodies of mice treated with QJZ were significantly down-regulated, C3 and C4 were significantly up-regulated. QJZ also alleviated proteinuria, decreased SCr and BUN levels and minimized renal histopathological changes. In addition, QJZ affected the expression of GAS5/miR-21/sprouty1 axis and the phosphorylation of ERK/CREB pathway in renal tissues. QJZ bears therapeutic ability on healing renal injury in MRL/lpr mice. These effects may be achieved by regulating the GAS5/miR-21/sprouty1 axis and inhibiting the ERK/CREB pathway, thus improving the excessive proliferation of glomerular mesangial cells.