We explored the role of commensal Neisseria in the emergence of third-generation cephalosporin-resistant N. meningitidis. Cefotaxime resistance-conferring penA795 was prevalent among commensal Neisseria isolates in Shanghai, China, and was acquired by a serogroup C quinolone-resistant sequence type 4821 N. meningitidis, Nm507, causing fulminant meningitis in an unvaccinated 2-year-old child.