Mycobacterium abscessus (Mab) is highly drug resistant, and understanding regulation of antibiotic resistance is critical to future antibiotic development. Regulatory mechanisms controlling Mab’s β-lactamase (Bla _Mab) that mediates β-lactam resistance remain unknown. S. aureus encodes a prototypical protease-mediated two-component system BlaRI regulating the β-lactamase BlaZ. BlaR binds extracellular β-lactams, activating an intracellular peptidase domain which cleaves BlaI to derepress blaZ. Mtb encodes homologs of BlaRI, that regulate the Mtb β-lactamase, blaC, but also additional genes related to respiration. We identified orthologs of blaRI_Mtb in Mab and hypothesized that they regulate bla_Mab. Surprisingly, neither deletion of blaRI_Mab nor overexpression of only blaI_Mab altered bla_Mab expression or β-lactam susceptibility. However, BlaI _Mab did bind to conserved motifs upstream of several Mab genes involved in respiration, yielding a putative regulon that partially overlapped with BlaI _Mtb. Prompted by evidence that respiration inhibitors including clofazimine (CFZ) induce the BlaI regulon in Mtb, we found that CFZ triggers induction of blaIR_Mab and its downstream regulon. Highlighting an important role for BlaRI _Mab in adapting to disruptions in energy metabolism, constitutive repression of the BlaI _Mab regulon rendered Mab highly susceptible to CFZ. In addition to our unexpected findings that BlaIR _Mab does not regulate β-lactam resistance, this study highlights the novel role for mycobacterial BlaRI-type regulators in regulating electron transport and respiration.