The ADP ribosyltransferases (PARPs 1–17) regulate diverse cellular processes, including DNA damage repair. PARPs are classified on the basis of their ability to catalyze poly-ADP-ribosylation (PARylation) or mono-ADP-ribosylation (MARylation). AlthoughPARP9mRNA expression is significantly increased in progressive tuberculosis (TB) in humans, its participation in host immunity to TB is unknown. Here, we show thatPARP9mRNA encoding the MARylating PARP9 enzyme was upregulated during TB in humans and mice and provide evidence of a critical modulatory role forPARP9in DNA damage, cyclic GMP–AMP synthase (cGAS) expression, and type I IFN production during TB. Thus,Parp9-deficient mice were susceptible toMycobacterium tuberculosisinfection and exhibited increased TB disease, cGAS and 2′3′-cyclic GMP-AMP (cGAMP) expression, and type I IFN production, along with upregulation of complement and coagulation pathways. EnhancedM. tuberculosissusceptibility is type I IFN dependent, as blockade of IFN α receptor (IFNAR) signaling reversed the enhanced susceptibility ofParp9–/–mice. Thus, in sharp contrast to PARP9 enhancement of type I IFN production in viral infections, this member of the MAR family plays a protective role by limiting type I IFN responses during TB.