Gonococcal infections, caused by Neisseria gonorrhoeae (Ng), are treated with antibiotics. However, multidrug-resistant (MDR) strains of Ng have become increasingly prevalent, rendering many antibiotics ineffective. Lipooligosaccharide phosphoethanolamine transferase A (EptA), which modifies lipid A in Ng, plays a crucial role in bacterial resistance to the immune defence, cationic antimicrobial peptides (CAMP) such as LL-37. We have discovered a new class of small molecules, INH-2, which effectively inhibits EptA in antimicrobial-susceptible (AMS) isolates and enables human macrophages to clear the infection. This study aimed to determine if INH-2 could overcome resistance in MDR Ng strains. INH-2 was tested for improved potency in assays for sensitivity to CAMP LL-37 using MDR- and extensively drug-resistant (XDR) isolates (WHO P, G, X, and Y). INH-2 restored sensitivity to LL-37 in wild-type Ng, achieving similar minimum inhibitory concentrations (MICs) as the isogenic ∆eptA mutant across all strains tested. A checkboard assay was performed using penicillin, ceftriaxone, gentamicin and azithromycin. INH-2 synergised with sub-inhibitory concentrations of β-lactam antibiotics and LL-37 to kill the XDR strain WHO X. INH-2 treatment of WHO X infected cell lines treated resulted in a 50% reduction in gonococcal load which is comparable to the ∆eptA mutant. Importantly, INH-2 potentiated the cure of WHO X infected RAW macrophage cell lines treated with sub-inhibitory concentrations of penicillin and ceftriaxone. Furthermore, INH-2 showed no toxicity towards the ∆eptA mutant in any assay. In conclusion, INH-2 is a novel EptA inhibitor that enhances the effectiveness of both innate immune responses and existing antibiotics against MDR and XDR Ng. Its ability to break resistance to penicillin and ceftriaxone resistance in otherwise untreatable isolates such as WHO X provides a strategy for restoring efficacy of these antibiotics for clinical use.