Objective To investigate the intervention effect of the traditional Chinese medicine Shendi Granule on renal endoplasmic reticulum stress and podocyte autophagy in rats with nephritis induced by cationic bovine serum albumin (C-BSA). Methods A total of 40 male Sprague-Dawley rats were randomly divided into normal group, model group, Shendi Granule group, and valsartan group, with 10 rats in each group. The rats in the Shendi Granule group were given Shendi Granule solution 4.0 g/kg by gavage every day, those in the valsartan group were given the suspension of valsartan capsules 20 mg/kg by gavage every day, and those in the normal group and the model group were given normal saline by gavage. Colorimetry was used to measure 24-hour urinary protein (24hUPro), and Western blot was used to measure the protein expression levels of glucose-regulated protein 78 (GRP78), CHOP, nephrin, podocalyxin, and Beclin 1 and microtubule-associated protein 1 light chain 3-Ⅱ (LC3-Ⅱ)/microtubule-associated protein 1 light chain 3-Ⅰ (LC3-Ⅰ) ratio in the kidney. A transmission electron microscope was used to observe glomerular injury in renal tissue. Results Compared with the normal group, the model group had a significant increase in 24hUPro (P<0.05), significant increases in the relative protein expression levels of GRP78, CHOP, and Beclin 1 and LC3-Ⅱ/LC3-Ⅰ ratio in renal tissue (P<0.05), and significant reductions in the relative protein expression levels of nephrin and podocalyxin (P<0.05). Compared with the model group, the Shendi Granule group and the valsartan group had a significant reduction in 24hUPro (P<0.05), significant reductions in the expression levels of GRP78 and CHOP (P<0.05), and significant increases in the protein expression levels of nephrin and podocalyxin (P<0.05); compared with the model group, the Shendi Granule group had significant increases in the expression level of Beclin 1 and LC3-Ⅱ/LC3-Ⅰ ratio (P<0.05), and the valsartan group showed slight increases (P>0.05); compared with the valsartan group, the Shendi Granule group had significantly greater changes in the expression levels of GRP78, CHOP, podocalyxin, and Beclin 1 and LC3-Ⅱ/LC3-Ⅰ ratio (P<0.05). Conclusion Enhanced endoplasmic reticulum stress and podocyte injury are observed in rats with C-BSA nephritis, and there is also a significant increase in podocyte autophagy activity. The traditional Chinese medicine Shendi Granule can enhance autophagy activity and alleviate podocyte injury mediated by endoplasmic reticulum stress, thereby reducing the level of urinary protein in rats with C-BSA nephritis.