Given the consistently poor prognoses for some of the most difficult-to-treat cancers, rapidly translatable treatment regimens that offer improvements in outcomes are much needed. The repurposing of FDA approved non-cancer drugs presents an opportunity to design clinically feasible, novel combinations of therapies with a mechanistic rationale, to overcome resistance and survival pathways that render many current treatments ineffective. Tetracyclines are a class of antibiotics that demonstrate potential for such repurposing, as they have also been shown by others to affect a wide range of targets in cancer. Notably, the unique structure of tetracyclines allows them to act through both light activated and non-light mediated mechanisms. While light activation of tetracyclines can result in singlet oxygen production, their non-light mediated targets include inhibition of DNA repair enzymes and modulation of hypoxia-inducible markers, among others. With these mechanisms in mind, we seek to elucidate the benefit of including tetracyclines as part of an already promising, mechanistically cooperative photochemotherapy combination for ovarian cancer. In ovarian cancer, the dismal rates of recurrence and survival associated with the aggressive disease further emphasize the need to mechanistically reinforce treatments regimens. Thus, the results will highlight insights into the cooperative effect of repurposed tetracyclines on treatment response and molecular markers, both in vitro and in a challenging mouse model of disseminated ovarian cancer.