Abstract Background Invasive meningococcal disease (IMD) is an acute, highly transmissible and potentially fatal disease caused by Neisseria meningitidis. Prompt antimicrobial therapy and prophylaxis are recommended, where penicillin or ciprofloxacin are the available choices. However, the emergence of resistant isolates of N. meningitidis poses a challenge for antimicrobial therapy. Objectives To describe the clinical, epidemiological and biological characteristics of six penicillin- and ciprofloxacin-resistant, culture-confirmed IMD cases reported in El Salvador, Central America, between 2017 and 2019. Methods Following the detection of six patients presenting with IMD in El Salvador, clinical data were collected and epidemiological action plans conducted. Isolates were subjected to antimicrobial susceptibility testing by broth microdilution and WGS for genotyping and molecular characterization analysis, including phylogeny comparison with global sequences available from public databases. Results A total of six IMD cases caused by N. meningitidis serogroup Y, resistant to both penicillin (MIC >8.0 mg/L) and ciprofloxacin (MIC 0.125 mg/L), were detected from 2017 to 2019. Genomic analysis showed that penicillin resistance was mediated by the production of β-lactamase ROB-1. Ciprofloxacin resistance was attributed to an amino acid substitution in DNA gyrase (T91I). All isolates were classified as ST3587, clonal complex 23, and were genetically highly similar, based on core-genome SNP analysis. Conclusions To the best of our knowledge, we report the first cases of MDR N. meningitidis causing IMD in Latin America. Our findings highlight the emergence of this potential public health threat, with a profound impact on the efficacy of IMD treatment and prophylaxis protocols.