The interactions between pathogens and host cells and the way by which the immune response is modulated during this process ultimately dictate the fate of infection. Host phagocytes exposed to Mycobacterium tuberculosis (M. tuberculosis) sense microbial-associated molecular patterns and activate a series of signaling pathways. In this setting, activation of the nuclear factor κB (NF-κB) initiates transcription of several key genes involved in orchestration of antimycobacterial effector functions. This review describes these major pathways that govern the outcome of host phagocytes infected with M. tuberculosis. Furthermore, we highlight evidence of how M. tuberculosis modulates activation of NF-κB pathways to evade the host antimycobacterial defense.