The failure of conventional vaccines or antimicrobials to combat newly emerging pathogens such as new influenza viruses or antibiotic-resistant bacteria provides significant challenges in the identification of innovative therapeutic approaches and targets for microbial infections. Such therapies, directed towards host-cell molecules, may represent alternative options where conventional approaches face difficulties. We will largely focus on those strategies that directly target the host inflammatory response, specifically those that result in the activation of the nuclear transcription factor (NF)-κB. NF-κB plays a central role in the cellular stress response and in inflammation by controlling the expression of a network of inducers and effectors that define responses to pathogens. Therefore, the modulation of NF-κB activation and its signaling pathway offer an exceptional therapeutical strategy that could benefit from targeting a single host regulatory pathway. The use of NF-κB inhibitors or enhancers will be possible only if modulation between the host's and pathogen's advantage can be reached. Since different pathogens have developed various mechanisms to alter the activation of NF-κB, the present review will mainly focus on the role of NF-κB in microbial infections, highlighting its importance as a therapeutic target and reviewing the current understanding of how NF-κB inhibition can be considered a potential paradigm for the development of novel antimicrobial therapies.