<p>In the past few decades, invasive mycosis has become a growing threat to global health, afflicting millions of people and claiming the lives of more than 1.5 million patients every year. Moreover, the economic burden of mycotic infections has become increasingly exhausting especially with the recent increases in the number of the high-risk population, the immunocompromised individuals. In the USA, the cost incurred by mycotic infections was estimated to be of more than $7.2 billion only in 2017. Of particular concern, <i>Candida</i> species are the most common fungal pathogens that infect humans, resulting in considerable morbidities and mortality rates that often exceed 50%. Unfortunately, the antifungal drug discovery is currently unable to keep pace with the urgent demand for more effective therapeutic options. Further complicating the situation is the recent emergence of multidrug-resistant species such as <i>Candida</i> <i>auris</i>, triggering outbreaks of deadly Candidemia across the globe. Given the risks inherent to the traditional de-novo drug discovery, combinatorial therapeutics stands out as a promising tool to hamper drug resistance and extend the clinical utility of the existing drugs. In this study, we assembled and screened ~3147 FDA-approved drugs and clinical molecules against fluconazole-resistant <i>C. albicans</i> and <i>C. auris</i> isolates, for the aim of restoring the antifungal activity of azole antifungals against drug-resistant <i>Candida </i>species. The screen revealed five promising hits: pitavastatin (antihyperlipidemic), ospemifene (estrogen receptor modulator), sulfa antibacterial drugs, lopinavir (antiviral), and aprepitant (antiemetic).</p> <p>All identified hits demonstrated variable azole chemosensitizing activities depending on the tested <i>Candida</i> species and the azole drug. Pitavastatin displayed broad-spectrum synergistic interactions with both fluconazole and voriconazole against isolates of <i>C. albicans</i>, <i>C. glabrata</i>, and <i>C. auris</i>. Ospemifene was able to interact synergistically with itraconazole against multiple fungal isolates including <i>Candida</i>, <i>Cryptococcus</i>, and <i>Aspergillus</i> species. Sulfa drugs displayed potent synergistic activities with different azoles against <i>C. albicans</i>, however, a limited efficacy was observed against efflux-hyperactive isolates such as <i>C. auris</i>. On the other hand, both lopinavir and aprepitant exerted potent and broad-spectrum synergistic activities with itraconazole and were effective against multiple <i>Candida</i> species including <i>C. albicans</i>, <i>C. auris</i>, <i>C. glabrata</i>, <i>C. krusie</i>, <i>C. tropicalis</i>, and <i>C. parapsilosis</i>. Furthermore, using <i>Caenorhabditis elegans</i> as an infection model, all drug combinations significantly reduced the fungal burden in the infected nematodes and significantly prolonged their survival as compared to single-drug treatments. Multiple phenotypic and molecular assays indicted that the identified hit compounds use distinct mechanisms to enhance the antifungal activity of azole drugs. These mechanisms include efflux pump inhibition, interference with the folate biosynthesis and disturbance of iron homeostasis. Taken together, this study reveals novel and potent azole chemosensitizing agents effective against multiple azole-resistant isolates and opens the door for more investigations to assess their clinical potential in human medicine as promising antifungal adjuvants.</p>