Abstract Direct‐acting antivirals (DAAs) have become an effective first‐line treatment for chronic hepatitis C (CHC), and the fixed‐dose combination of sofosbuvir (SOF) and velpatasvir (VEL) is one of the most important pangenotypic DAA regimen according to present treatment guideline. The association between SOF‐based regimens and renal toxicity remains controversial. A total of 953 patients including 130 with estimated glomerular filtration rate (eGFR) ≤ 60 mL/min/1.73m 2 and 823 with eGFR > 60 mL/min/1.73m 2 receiving SOF/VEL therapy for 12 weeks were enrolled in this study. The eGFR was assessed at baseline, end of treatment (EOT), and 12 weeks after completion of the therapy (end of follow‐up, EOF). The eGFR in patients with eGFR ≤ 60 mL/min/1.73m 2 increased from baseline (47.89 ± 10.25 mL/min/1.73m 2 ) to EOT (51.65 ± 15.92; P  < .001) and EOF (51.51 ± 14.46 mL/min/1.73m 2 ; P  < .05). The eGFR in patients with eGFR > 60 mL/min/1.73m 2 at baseline (91.52 ± 22.06 mL/min/1.73m 2 ) was lower at EOT (90.37 ± 22.3; P  < .05), with no difference between EOT and EOF ( P = .06). Multivariable analysis showed that a higher serum albumin level was associated with a lower risk of eGFR decrease at EOT, and the patients with baseline eGFR > 60 mL/min/1.73m 2 were associated with a higher risk of eGFR decrease at EOF. The rates of sustained virologic response 12 weeks after treatment cessation (SVR12) were 99.2% in per‐protocol analysis, and the most common adverse events were fatigue (4.7%), abdominal discomfort (4.5%), and skin itching (3.7%). In conclusion, renal function improved after the SOF/VEL treatment in patients with CHC and chronic kidney disease. Thus, SOF/VEL was safe, effective, and tolerable in these patients.