Cleistocalyx operculatus is ubiquitous and known by folk experiences for its antimicrobial properties, thus promising as a low-cost green pesticide. In this work, the plant ethanol extract was investigated against Cercospora nicotianae, a pathogenic fungus implicated in the leaf spot in Pennywort. Characterisation of the plant extract showed 21 identifiable constituents (1-21), with the major components: 4',5'-dimethoxy-2'-hydroxy-4-methylchalcone (21; 41.71 %), phytol (15; 8.46 %), and 5.7-dimethoxyflavanone (20; 5.20 %). The in vitro antifungal screening of the extract revealed potent inhibitory capacity up to 7 days after inoculation (concentration = 9.54 mg.mL-1). The inhibitory potential was predicted by docking simulation, i.e., 19-Q6DQW3 (DS - 10.7 kcal.mol-1; DSmax -12.7 kcal.mol-1) > 21-Q6DQW3 (DS -10.3 kcal.mol-1; DSmax -11.9 kcal.mol-1) > 20-Q6DQW3 (DS -10.3 kcal.mol-1; DSmax -11.7 kcal.mol-1). The chemical potentiality was derived from quantum calculation, i.e., 22 (-1172.77 a.u.) > 21 ≈ 19 (approx. -1000 a.u.) > 20 (-ca. -950 a.u.) for chemical stability, and 3 (3.40 Debye), 15 (2.47 Debye), and 5 (2.03 Debye) for physical compatibility. The suitability for biological and pesticidal applications was justified by physicochemical analyses. The results revealed a firm correlation between the extracted major constituents (20 and 21) and the total antifungal activity against C. nicotianae, thus encouraging its local usage.