Downy mildew (caused byPlasmopara viticola) and gray mold (caused byBotrytis cinerea) are fungal diseases that significantly impact grape production globally. Cytochrome b plays a significant role in the mitochondrial respiratory chain of the two fungi that cause these diseases and is a key target for quinone outside inhibitor (QoI)-based fungicide development. Since the mode of action (MOA) of QoI fungicides is restricted to a single active site, the risk of developing resistance to these fungicides is deemed high. Consequently, using a combination of fungicides is considered an effective way to reduce the development of QoI resistance. Currently, there is little information available to help in the selection of appropriate fungicides. This study used a combination of in silico simulations and quantitative structure–activity relationship (QSAR) machine learning algorithms to screen the most potent QoI-based fungicide combinations for wild-type (WT) and the G143A mutation of fungal cytochrome b. Based on in silico studies, mandestrobin emerged as the top binder for both WTPlasmopara viticolaand WTBotrytis cinereacytochrome b. Famoxadone appeared to be a versatile binder for G143A-mutated cytochrome b of bothPlasmopara viticolaandBotrytis cinerea.Thiram emerged as a reasonable, low-risk non-QoI fungicide that works on WT and G143A-mutated versions of both fungi. QSAR analysis revealed fenpropidin, fenoxanil, and ethaboxam non-QoIs to have a high affinity for G143A-mutated cytochrome b ofPlasmopara viticolaandBotrytis cinerea. Above-QoI and non-QoI fungicides can be considered for field studies in a fungicide management program againstPlasmopara viticola- andBotrytis cinerea-based fungal infections.