Robust interferon (IFN) response signatures are associated with M. tuberculosis (Mtb) infection in patients and animal models. These signatures are currently being explored for their potential as diagnostic biomarkers as well as treatment surveillance. Whereas IFNg is central to the immune control of Mtb infection, type I IFNs have been implicated in undermining effective immune responses to control Mtb. The molecular drivers and functions of type I IFNs during Mtb infection are subject of intensive investigation. cGAS/STING as well as NOD2 have been identified to promote type I IFN responses during Mtb infection in an ESX-1-dependent manner. We discovered that the unconventional Toll-like receptor Radioprotective 105 kDa (Rp105, CD180) is a driver of the type I IFN response during mycobacterial infection. Rp105-deficient macrophages displayed reduced IFN-β secretion in response to infection with the attenuated M. bovis BCG, which lacks ESX-1. This was associated with decreased phosphorylation of TANK Binding Kinase 1 (TBK1), impaired Interferon Regulatory Factor 3 (IRF3) nuclear translocation, and reduced mRNA expression of Ifnb1 in Rp105-deficient macrophages when compared to wild type control cells. In vivo, Rp105 contributed to the local induction of Ifnb1 expression in BCG-infected tissues. In contrast to BCG, infection of macrophages with Mtb strains across a virulence spectrum revealed contributions of Rp105 to promoting IFN-β release by infected macrophages rather than Ifnb1 mRNA expression. These data reveal multi-modal contributions of Rp105 to type I IFN responses during mycobacterial infection and underpin the functions of Rp105 as an innate immune receptor for phylogenetically diverse mycobacteria.