The emergence of drug-resistant fungal pathogens poses great threats to an increasing number of vulnerable populations worldwide, and the need for novel antifungal agents is imperative. In this work, a series of lipo-γ-AA peptides were synthesized and evaluated for their biological activities. One lead, MW<b>5</b>, exhibited potent and broad-spectrum antifungal activity. In addition, MW<b>5</b> potently boosted the efficacy of fluconazole against clinical azole-resistant <i>Candida</i> isolates. Mechanistic investigation showed that the lead compound disrupted the cell membrane, significantly boosted the production of reactive oxygen species, and undermined the function of the efflux pump, thus resensitizing drug-resistant <i>Candida albicans</i> to fluconazole. Notably, coadministration of MW<b>5</b> and fluconazole exhibited potent <i>in vivo</i> antifungal activity in a murine model of mucocutaneous candidiasis. Our results demonstrated that lipo-γ-AA peptides have great promise for use alone or in combination to combat drug-resistant <i>Candida</i> infections.