Necrotic lesions on leaves caused by Corynespora leaf spot (CLS) seriously threaten the quality and yield of cucumber in China. Corynespora cassiicola has developed different degrees of sensitivity to various fungicides due to its long-term and extensive application. In our work, the effect of isopyrazam and mefentrifluconazole on different life stages of C. cassiicola was examined. To determine the optimal effect of binary mixtures of isopyrazam and mefentrifluconazole, the two fungicides were mixed at different proportions. Furthermore, the disease suppression of isopyrazam, mefentrifluconazole, and their compound mixture against CLS was evaluated in greenhouse experiments. Ultraviolet (UV) mutagenesis and fungicide-selection methods were performed to assess the risk of resistance development. Among the three life stages tested, isopyrazam showed the weakest inhibition on mycelial growth, and mefentrifluconazole showed the strongest inhibition of germ tube elongation. According to Wadley's and cotoxicity coefficient methods, the optimal proportion of the two-component mixture of isopyrazam and mefentrifluconazole was 1:1. Isopyrazam, mefentrifluconazole, and their binary mixture at 1:1 reduced the disease severity of CLS on potted cucumber plants, with protective effects of 31.11, 24.65, and 42.12% and curative effect of 33.90, 37.48, and 42.84%, respectively. Compared with isopyrazam or mefentrifluconazole alone, the binary mixture of the two fungicides at 1:1 did not exert significant influence on the change of C. cassiicola sensitivity. Undoubtedly, such data will greatly facilitate the screening of new fungicides for CLS and resistance management.