To determine the prevalence of resistance to macrolides in Mycoplasma pneumoniae worldwide. Prior to 12 December 2020, PubMed, Web of Science, Scopus and Embase databases were searched for epidemiological studies of M. pneumoniae resistance. Two reviewers independently extracted data from included studies. The extracted data include sampling population, total sampling number, the number of resistant strains and the molecular subtype of resistant strains. The estimate of resistance prevalence was calculated using the random-effects model. A total of 17 873 strains were obtained from five continents and reported in 98 investigations between 2000 and 2020, with 8836 strains characterized as macrolide resistant. In summary, macrolide-resistant M. pneumoniae was most common in Asia (63% [95% CI 56, 69]). In Europe, North America, South America and Oceania, the prevalence was 3% [2, 7], 8.6% [6, 11], 0% and 3.3%, respectively. Over the last 20 years, the prevalence of macrolide-resistant M. pneumoniae has remained high in China (81% [73, 87]), with a significant increasing trend in South Korea (4% [1, 9] to 78% [49, 93], P < 0.0001). Furthermore, a point mutation at 2063 from A to G was mostly related to M. pneumoniae macrolide resistance. In terms of clinical outcomes, longer cough (mean difference [MD]: 2.93 [0.26, 5.60]) and febrile days (MD: 1.52 [1.12, 1.92]), and prolonged hospital stays (MD: 0.76 [0.05, 1.46]) might be induced by macrolide-resistant M. pneumoniae pneumonia. The incidence of macrolide-resistant M. pneumoniae varies globally, with eastern Asia having a greater degree of resistance. However, attention is also required in other areas, and antibiotic alternatives should be considered for treatment in high-prevalence countries.