Objective To investigate the regulatory effect of resveratrol ( RSV) targeting of SIRT1 ( silence information regulator) to activate the kelch-like ECH associated protein (Keap) 1-nuclear factor erythroid 2-related factor (Nrf)2-heme oxygenase (Ho)-1 pathway on calcium oxalate stone formation. Methods In this experiment, the optimal drug dose of RSV for human renal epithelial cells (HK-2) was screened by the Cell Counting Kit (CCK)8 method . HK-2 cells were randomly divided into four groups: control, oxalic acid, oxalic acid + RSV, and oxalic acid + RSV+ EX527. The cell viability of the preparation group was determined by the CCK8 method . Flow cytometry was used to detect the reactive oxygen species (ROS) production in each experimental group. The expression of Sirt1, Keapl, Nrf2, HO-1, transforming growth factor (TGF)-β1 and Smad2 were explored by western blotting and PCR experiments. A HK-2-small interfering RNA (siRNA) was constructed, and the above indicators were re-tested. Results Drug toxicity screening result showed that 500 nM was the optimal drug dose for the experiment. CCK8 suggested that RSV relieved the damage of HK-2 by oxalic acid. The Sirt1 inhibitor EX527 reversed the protective effect of RSV. The measurement of active oxygen levels showed that RSV reduced the production of active oxygen induced by sodium oxalate, and EX527 blocked the effect of RSV. Western blotting result showed that, compared with the sodium oxalate group, Sirt1, Keap1, Nrf2 and HO-1 expression was upregulated (P < 0. 01) while Smad2 expression was downregulated ( P < 0. 01). However, after applying EX527, the expression of related proteins upregulated by Sirt1 decreased. Quantitative PCR result showed that, compared with the sodium oxalate group, mRNA expression of TGF-β1 (P<0. 01), Smad2 (P<0. 05), Smad3 (P<0. 05) and Smad4 (P< 0. 01) were downregulated (P<0. 01) after RSV application, while Sirt1 mRNA expression was upregulated (P<0. 01). The application of EX527 reversed these effects. Western blotting result showed that, compared with the sodium oxalate group, Sirt1 expression was downregulated, and keap1, Nrf2 and HO-1 expression were downregulated after siRNA interference. When RSV treatment was applied after silencing of Sirt1 expression, RSV could not inhibit Smad2 activation. Conclusions This study showed that RSV had antioxidant effects on HK-2 cells through a mechanism that may involve Sirt1 activation to promote the expression of Keap1, Nrf2 and Ho-1, which further inhibits the production of TGF-β1, thereby inhibiting the generation of ROS.