BACKGROUND: Neisseria gonorrhoeae is one of the recognized global antimicrobial resistance priorities. Extended-spectrum cephalosporins, the last remaining reliable antimicrobial, increasingly fail to clear N. gonorrhoeae infections, especially pharyngeal gonorrhea, leading to limited future treatment options. METHODS: We conducted a systematic review and meta-analysis of gonococcal treatment failures and compared the minimum inhibitory concentrations (MICs) of isolates from pharyngeal and extra-pharyngeal anatomical sites (PROSPERO registration: CRD42020189101). RESULTS: The overall pooled mean MIC for cefixime was 0.17 mg/L (95% confidence interval [CI], 0.07-0.41 mg/L), and that for ceftriaxone was 0.10 mg/L (95% CI, 0.05-0.22 mg/L). For cefixime, the mean MIC estimates for pharyngeal and extrapharyngeal treatment failures were 0.05 mg/L (95% CI, 0.02-0.14 mg/L) and 0.29 mg/L (95% CI, 0.11-0.81 mg/L), and those for ceftriaxone were 0.09 mg/L (95% CI, 0.03-0.22 mg/L) and 0.14 mg/L (95% CI, 0.03-0.73 mg/L), respectively. The pooled mean MICs for pharyngeal isolates are below the phenotypic European Committee on Antimicrobial Susceptibility Testing resistance breakpoint for both antimicrobials (>0.125 mg/L). CONCLUSIONS: Our findings underscore the need to review the current resistance breakpoints used for pharyngeal infection, to establish international standards for MIC testing, and to advance efforts of the World Health Organization's global action plan to control the spread and impact of antimicrobial resistance in N. gonorrhoeae . Ongoing susceptibility testing of gonococcal isolates and surveillance of treatment failures are central to informing appropriate public health responses.