Objective To determine the effects of rixolipite granules on renal calcium oxalate calculi and protein kinase C (PKC)-nuclear factor erythroid-2-related factor 2 (Nrf2) signaling to antioxidant response elements (AREs). Methods Thirty-two specific pathogen-free Sprague Dawley rats were randomly allocated to four groups ( n= 8 each): a control group, a model group, a treatment group, and an inhibitor group. All of the rats except the controls were administered ethylene glycol and ammonium chloride in their diet to induce urinary calcium oxalate calculus formation within 28 days. The treatment group was also administered 10. 0 g / kg Lengzhu Paishi granules, and the inhibitor group was administered 30 mg / kg r031-8220 once daily by gavage for 28 days. Afterward, 24 h urine volume, urine pH, urinary oxalic acid (Ox) concentration, the circulating Ca²⁺ and Mg²⁺ concentrations and the 24 h urinary output of each, blood urea nitrogen (BUN), and circulating creatinine (Cr) concentrations were measured. The protein expression of PKC, Keap1, Nrf2 was characterized using von Kossa staining and Western blot. Results The model group had significantly lower 24 h urine volume, urine pH, circulating Mg²⁺ , urinary Mg²⁺ , and renal superoxide dismutase activity than the control group; and the Ox, circulating and urinary Ca²⁺ , renal malondialdehyde concentration, reactive oxygen species fluorescence intensity, and PKC, Keap1, and Nrf2 protein expression were significantly higher (P<0. 05). Lengzhu Paishi granule treatment significantly ameliorated all these effects (P<0. 05). There was no significant difference between the two groups (P>0. 05). Conclusions Lengzhu Paishi granules prevent the pathological changes associated with renal calcium oxalate calculus formation in rats, which may be mediated through the activation of the antioxidant signaling pathway PKC- Nrf2 / ARE and a reduction in oxidative stress.