Among the different xanthones previously isolated from the stem bark of Calophyllum caledonicum, caledonixanthone E presented the strongest activity (MIC (80) = 8 microg/mL) in acidic conditions (pH 3) against the human pathogenic fungus Aspergillus fumigatus. Phase-contrast microscopy studies suggested the assembly or synthesis of cell wall components as the target of the drug. Moreover, the use of fluorescent lectins further supported an impact of caledonixanthone E on the synthesis of chitin, the major structural polysaccharide of the fungal wall. These results suggest that caledonixanthone E may be an interesting model for the design of new antifungal drugs.