Since the first report of erythromycin-resistant Bordetella pertussis (B. pertussis) in Arizona in 1994, macrolide-resistant strains have emerged worldwide, threatening pertussis control. This systematic review and meta-analysis aimed to quantify the prevalence and temporal trends of this resistance. Four databases (PubMed, Embase, Cochrane Library, Web of Science) were searched for studies on B. pertussis antimicrobial susceptibility through December 2024. Among 57 included studies (1994–2024), pooled resistance rates (breakpoint ≥32 mg/L) were: erythromycin 21% (95% CI 11–32%), azithromycin 25% (95% CI 12–40%), clarithromycin 15% (95% CI 4–30%), and clindamycin 49% (95% CI 28–70%). Subgroup analyses by country, year, and test method are presented. No trimethoprim/sulfamethoxazole (STX) resistance was reported. Six Japanese isolates showed high-level nalidixic acid resistance (MIC >256 mg/L). Seventy-seven studies contributed to MIC90 data for carbapenems, tetracyclines, aminoglycosides, quinolones, macrolides, cephalosporins, and others. Selected penicillins and intravenous third-generation cephalosporins demonstrated strong in vitro activity, suggesting alternative treatment options. Macrolide-resistant B. pertussis has increased significantly over the past decade. Due to the high burden of antibiotic resistance in China, enhanced surveillance is warranted, while continued monitoring in other countries also remains necessary.