This study aimed to investigate hydrophilic compounds and their antifungal activity from the inner and outer bark of Swietenia macrophylla. The hydrophilic compound of S. macrophylla in the inner and outer bark parts was detected by Gas Chromatography Mass Spectra (GC–MS) and antifungal activity was determined through the inhibition of sample to growth of Phanerochaete chrysosporium. The detection of hydrophilics observed several sugar and phenolic compounds in inner and outer bark of S. macrophylla. The antifungal activity in outer bark sample was greater (IC50 of 1536.27 ± 18.02 µg/ml) than that of inner bark (2433.89 ± 103.62 µg/ml). This suggests that the presence of (+)-catechin, (−)-epicatechin, and pyrocatechol in the outer bark layer tends to inhibit the white-rot fungal activity. Therefore, the phenolic compounds of S. macrophylla bark is potent for natural preservative.