There is an urgent need to identify new treatments for fungal infections. By combining sub-lethal concentrations of the known antifungals fluconazole, caspofungin, amphotericin B, terbinafine, benomyl, and cyprodinil with ∼3,600 compounds in diverse fungal species, we generated a deep reservoir of chemical-chemical interactions termed the Antifungal Combinations Matrix (ACM). Follow-up susceptibility testing against a fluconazole-resistant isolate of C. albicans unveiled ACM combinations capable of potentiating fluconazole in this clinical strain. We used chemical genetics to elucidate the mode of action of the antimycobacterial drug clofazimine, a compound with unreported antifungal activity that synergized with several antifungals. Clofazimine induces a cell membrane stress for which the Pkc1 signaling pathway is required for tolerance. Additional tests against additional fungal pathogens, including Aspergillus fumigatus, highlighted that clofazimine exhibits efficacy as a combination agent against multiple fungi. Thus, the ACM is a rich reservoir of chemical combinations with therapeutic potential against diverse fungal pathogens. Display omitted •The Antifungal Combination Matrix reports 1,550 antifungal drug combinations•ACM combinations act against fungal pathogens including azole-resistant C. albicans•Clofazimine potentiates antifungals in diverse fungi by targeting membrane function•Clofazimine potentiates caspofungin in an invertebrate model of fungal pathogenesis There is a dire need for new antifungal therapies. To address this necessity, Robbins et al. screened ∼86,000 unique chemical combinations for activity against fungi. The authors find that the antimycobacterial drug clofazimine increases the efficacy of antifungals by disrupting membrane integrity. This study unveils a rich dataset for antifungal development.