Phytoalexin naringenin and phytohormone abscisic acid (ABA) play crucial roles in plant defense and physiology. This work encompassed both experimental and computational approaches to assess their antifungal efficacy against Phytophthora infestans and Magnaporthe oryzae. Naringenin and ABA, isolated from Desmodium sequax, exhibited significant in vitro antifungal activity against both pathogens. Naringenin was moderately active against M. oryzae in a dose-dependent manner, while ABA was not. The antifungal efficacy of ABA against P. infestans (IC50 = 19.7 μg/mL and IC90 = 72.0 μg/mL) was more potent when compared with that of naringenin (IC50 = 53.7 μg/mL and IC90 = 129.2 μg/mL). Computational models provided insights into their interactions with pathogenic enzymes. Naringenin emerged as a novel inhibitor of M. oryzae enzymes (1,3,8-trihydroxynaphthalene reductase and scytalone dehydratase); and together with ABA, it exhibited robust interactions with targeted P. infestans enzymes (chitin synthase and calmodulin). Ligand-based pharmacophore models were constructed for prospective P. infestans inhibitors. These findings highlight the mechanism and antifungal potential of naringenin and ABA and suggest their use as natural fungicides in sustainable agriculture.