Neisseria gonorrhoeae is a pathogenic bacterium that causes gonorrhea, a sexually transmitted infection responsible for an estimated 87 million new cases globally each year. Currently, antibiotics are the primary treatment for gonococcal infections; however, the emergence of multidrug-resistant (MDR) and extensively drug-resistant strains has rendered almost all classes of antibiotics ineffective. Lipooligosaccharide phosphoethanolamine (PEA) transferase A, EptA, is a member of the YhjW/YjdB/YijP superfamily and is responsible for the decoration of PEA to lipid A in the pathogenic Neisseria. The PEA-decorated lipid A is essential for bacterial resistance to killing by innate immune defenses such as macrophages, polymorphonuclear neutrophils, and cationic antimicrobial peptides (CAMPs). We propose that chemical inhibition of EptA will enable the innate immune system to clear gonoccocal infections. Therefore, the goal of our study was to investigate the efficacy and potency of novel EptA inhibitors in facilitating bacterial killing by innate immune defenses (CAMP LL-37 and macrophages). The minimal inhibitory concentration (MIC) of LL-37 for the (WT) N. gonorrhoeae strain FA1090 was greater than 12.8 µM while the ∆eptA mutant was killed by 3.2 µM. Six compounds increased the sensitivity of WT to the same degree as the ∆eptA mutant, suggesting that these compounds inhibited EptA. These compounds did not exhibit bactericidal effects on the WT and ∆eptA strains in the absence of LL-37, indicating their non-toxicity in the absence of CAMP. Two lead compounds could abrogate the intracellular survival of MDR isolates in a post-infection treatment model in murine RAW 264.7 macrophages. Neither of these compounds were affected by multidrug efflux pump MtrCDE. The combination of compound 3C11 and polymyxin B showed a low potential for the development of polymyxin B resistance, as compared to the exposure of N. gonorrhoeae strain FA1090 to sub-MIC of polymyxin B alone. In conclusion, we successfully identified a group of compounds that could assist the innate immune defenses to eliminate N. gonorrhoeae by inhibiting enzyme EptA.