This study aimed to examine the efficacy and safety of nirmatrelvir/ritonavir (Paxlovid) for COVID-19. PubMed, Cochrane Library, Web of Science, medRxiv, and Google Scholar were searched to identify the relevant evidence up to November 10, 2022. The reference lists of key studies were also scanned to find additional records. The quality of the studies was evaluated using the Cochrane tools for assessing risk of bias. The Comprehensive Meta-Analysis software version 3.0 was employed for data analysis. Twenty-three studies involving 314353 patients were included in the analysis. The findings of the meta-analysis showed a significant difference between the Paxlovid and no- Paxlovid groups in terms of mortality rate (odds ratio [OR] = 0.25, 95% confidence interval [CI]: 0.14 to 0.45), hospitalization rate (OR = 0.40, 95% CI: 0.24 to 0.69), polymerase chain reaction (PCR) negative conversion time (mean difference [MD] = -2.46, 95% CI: -4.31 to - 0.61), and hospitalization or death rate (OR = 0.17, 95% CI: 0.06 to 0.46). However, no significant difference was observed between two groups in terms of COVID-19 rebound (OR = 0.84, 95% CI: 0.67 to 1.04), emergency department visit (OR = 0.75, 95% CI: 0.45 to 1.24), ICU admission (OR = 0.37, 95% CI: 0.13 to 1.01), and adverse events (OR = 2.20, 95% CI: 0.42 to 11.47). The results of the present study support the efficacy and safety of Paxlovid in the treatment of patients with COVID-19. Further research is needed to investigate the COVID-19 rebound after Paxlovid treatment. This article is protected by copyright. All rights reserved.