Over the past several years, much has been revealed about the roles of autophagy and the mechanisms by which the autophagic pathway activates the host innate effector response against Mycobacterium tuberculosis (Mtb) infection. In response to invading mycobacteria, the host innate immune system not only recognizes pathogen motifs through innate receptors, it also produces appropriate effector proteins, including cytokines. These innate signals activate or regulate autophagic pathways during infection. It is now clear that vitamin D and functional vitamin D receptor signaling are critical in the activation of autophagic defenses against Mtb in human cells. Immunity-related GTPase family M proteins, including the cationic antimicrobial protein cathelicidin and autophagic receptor p62, participate in autophagic pathways that enhance antimicrobial activity against mycobacteria. Moreover, reactive oxygen species mediate antibacterial autophagy and successful antimicrobial responses during antibiotic chemotherapy. Recent work has also shown that pathogenic Mtb can be targeted by selective autophagy through an ESX-1 type VII secretion system. Here, we review the triggers, host factors, and intracellular pathways that regulate host autophagy and its impact on antimicrobial host defenses during mycobacterial infection.