is the most common cause of fungal infection. The emergence of drug resistance leads to the need for novel antifungal agents. We aimed to design naphthofuranquinone analogs to treat drug-resistant for topical application on cutaneous candidiasis. The time-killing response, agar diffusion, and live/dead assay of the antifungal activity were estimated against 5-fluorocytosine (5-FC)- or fluconazole-resistant strains. A total of 14 naphthofuranquinones were compared for their antifungal potency. The lead compounds with hydroxyimino (TCH-1140) or -acetyl oxime (TCH-1142) moieties were the most active agents identified, showing a minimum inhibitory concentration (MIC) of 1.5 and 1.2 μM, respectively. Both compounds were superior to 5-FC and fluconazole for killing planktonic fungi. Naphthofuranquinones efficiently diminished the microbes inside and outside the biofilm. TCH-1140 and TCH-1142 were delivered into -infected keratinocytes to eradicate intracellular fungi. The compounds did not reduce the burden inside the macrophages, but the naphthofuranquinones promoted the transition of fungi from the virulent hypha form to the yeast form. In the skin mycosis mouse model, topically applied 5-FC and TCH-1140 reduced the load from 1.5 × 10 to 5.4 × 10 and 1.4 × 10 CFU, respectively. The infected abscess diameter was significantly decreased by TCH-1140 (3-4 mm) as compared to the control (8 mm). The disintegrated skin-barrier function induced by the fungi was recovered to the baseline by the compound. The data support the potential of TCH-1140 as a topical agent for treating drug-resistant infection without causing skin irritation.