SummaryCandida kefyr is an emerging pathogen able to cause disseminated infection, especially in immunocompromised patients. Although guidelines for the treatment of invasive candidiasis have been published, no specific recommendations against C. kefyr are available. We determine the in vitro killing activity of amphotericin B (AMB), fluconazole (FLC) and caspofungin (CFG) as well as their efficacy in a murine model of systemic infection by two C. kefyr strains. Time‐kill curves of AMB, FLC and CFG were determined in final volumes of 10 ml containing the assayed drugs ranged from 0.03 to 32 μg ml−1 at different time points and efficacy of the drugs was evaluated in a systemic model of candidiasis, conducted in immunosuppressed mice, through survival, (1→3)‐β‐D‐glucan levels in serum and fungal load in kidneys. AMB and CFG showed fungicidal and FLC fungistatic activity against both isolates. The three drugs were able to reduce fungal burden in kidneys and (1→3)‐β‐D‐glucan concentration in serum of infected mice, with CFG showing the highest efficacy, followed by FLC. In conclusion, CFG showed efficacy over AMB and FLC against the systemic candidiasis by C. kefyr. The established epidemiological cut‐off for anidulafungin seems the best indicator of outcome for echinocandins.