Activity-guided fractionation of the 95% ethanol extract from the stem bark of Iryanthera megistophylla led to the isolation of two new compounds, named megislignan [2,3-dimethyl-4-(4-methoxyphenyl)-6-hydroxynaphthalene] (1) and megislactone [(2R,3R,4R)-3-hydroxy-4-methyl-2-(hexacos-17-enyl)butanolide] (2), along with seven known compounds, grandinolide (3), iryantherin K (4), iryantherin L (5), cinchonain I b (6), cinchonain I a (7), procyanidin B-2 (8), and cinchonain IIa (9). The structures of the new compounds were elucidated by spectral data interpretation. Isolates were evaluated for their antibacterial, antifungal, antiviral, and antiacetylcholinesterase activities.