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. It is well established that IFNg is central to the immune control of Mtb infection. In contrast, type I IFNs have been implicated in undermining effective immune responses to control Mtb. In recognition of their great potential as targets for host directed immunotherapy in tuberculosis, 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. Both cytosolic recognition mechanisms are dependent on ESX-1, a type VII secretion system of Mtb and major virulence factor. Here we show that the unconventional Toll-like receptor Radioprotective 105kDa (RP105, CD180) is a major driver of the type I IFN response during mycobacterial infection regardless of whether ESX-1 is expressed by the bacteria or not. RP105 deficient macrophages displayed impaired mRNA expression of Ifnb1 and IFN-inducible genes in response to viable and inactivated mycobacteria across a virulence spectrum. This was associated with decreased levels of phosphorylated TANK Binding Kinase 1 (TBK1) and nuclear translocation of interferon responsive factor 3 (IRF3). In vivo studies indicate that RP105 is the dominant driver of type I IFN responses during infection with attenuated, ESX-1-deficient mycobacteria. Overall, this work identifies a novel molecular mechanism of type I IFN induction during mycobacterial infection that acts independent of the central mycobacterial virulence factor ESX-1 and affirms the functions of RP105 as an innate immune receptor in the immune pathogenesis of mycobacterial infections.