Fifty-two kinds of N'-phenylhydrazides were successfully designed and synthesized. Their antifungal activity in vitro against five strains of C. albicans (Candida albicans) was evaluated. All prepared compounds showed varying degrees of antifungal activity against C. albicans and their MIC80 (the concentration of tested compounds when their inhibition rate was at 80%), TAI (total activity index), and TSI (total susceptibility index) were calculated. The inhibitory activities of 27/52 compounds against fluconazole-resistant fungi C. albicans 4395 and 5272 were much better than those of fluconazole. The MIC80 values of 14/52 compounds against fluconazole-resistant fungus C. albicans 5122 were less than 4 μg/mL, so it was the most sensitive fungus (TSIB = 12.0). A showed the best inhibitory activity against C. albicans SC5314, 4395, and 5272 (MIC80 = 1.9, 4.0, and 3.7 μg/mL). The antifungal activities of B and D against four strains of fluconazole-resistant fungi were better than those of fluconazole. The TAI values of A (2.71), B (2.13), and D (2.25) are the highest. Further exploration of antifungal mechanisms revealed that the fungus treated with compound A produced free radicals and reactive oxygen species, and their mycelium morphology was damaged. In conclusion, the N'-phenylhydrazide scaffold showed potential in the development of antifungal lead compounds. Among them, A, B, and D demonstrated particularly promising antifungal activity and held potential as novel antifungal agents.