Abstract Background Patients with kidney disease (KD) are at high risk of contracting COVID-19 and developing severe disease. There is still a lack of guidance regarding the treatment of COVID-19 in patients with KD. The safety and effectiveness of Azvudine in treating COVID-19 patients with KD remain unknown. Methods This study included 32,864 COVID-19 patients from nine centers in Henan Province, China. After applying the exclusion criteria and 2:1 propensity score matching, 438 and 219 participants in the Azvudine and Paxlovid groups, respectively, were subjected to analysis. Results Kaplan–Meier analysis revealed no significant differences in all-cause death or composite disease progression between the Azvudine and Paxlovid groups (all p values > 0.05). The same results were obtained in the Cox regression analysis after baseline characteristics adjustment. Three different sensitivity analyses contributed to the robustness of these findings. Subgroup analysis revealed that patients treated with Azvudine had a lower risk of composite disease progression than patients treated with Paxlovid did among patients with moderate disease (p = 0.016, HR: 0.51, 95% CI: 0.27–0.96). Safety data indicated that there was no difference in the incidence of most adverse events. Compared with the Paxlovid group, the Azvudine group had a lower incidence of hypophosphatemia (p = 0.008) and a lower PLT count (p = 0.045). Moreover, during the 15-day follow-up since drug administration, higher concentrations of lymphocytes were detected in the Azvudine group. Conclusions This study is the first to report that the safety and effectiveness of Azvudine are not inferior to those of Paxlovid in COVID-19 patients with KD. This study provides additional treatment options for COVID-19 patients with KD.