With the effectiveness of antimicrobials waning because of antimicrobial resistance, it is imperative that novel strategies are investigated for the treatment of infections. Antimicrobial blue light (aBL) is an innovative strategy that has proven efficacy against an array of pathogens, albeit, with different species having variable susceptibilities to the therapy. Quinine was discovered during the mid-17th century as a plant-derived potent antimalarial. More recently, its bactericidal properties were revealed, illustrating its potential as an antimicrobial adjuvant. Here we report a novel combination therapy, aBL+quinine hydrochloride (Q-HCL) for the treatment of multi-drug resistant infections. QHCL successfully potentiated the antimicrobial effects of aBL in numerous microbial pathogens of different etiologies, in vitro and in vivo. In addition, it synergistically improved the antimicrobial effects of aBL against bacterial biofilms. Raman spectroscopy revealed that concurrent exposure of aBL and Q-HCL improved uptake of Q-HCL into bacterial cells, when compared to the non aBL exposed sample. In addition, ultra-pure liquid chromatography (UPLC) revealed that Q-HCL increased the relative abundance of porphyrins in bacteria, suggesting the mechanism of this synergistic interaction is through increased production of intermediate photosensitizing porphyrins arising through perturbation of the heme biosynthesis pathway by Q-HCL. Genotoxic potential of the combination therapy against mouse skin tissue, was evaluated using the TUNEL assay, where it was revealed that a high dose exposure of aBL+Q-HCL (<3x the therapeutic dose) was not genotoxic to mouse skin tissue. In conclusion, the findings strongly suggest the potential of aBL+Q-HCL combination therapy as an alternative to traditional antibiotics for the treatment of localized infections.