The first phytochemical investigation of the twig extracts of Maclura fruticosa led to the isolation and identification of a new xanthone, maclurafruticosone (1), together with 14 known compounds (2-15). All compounds were elucidated using spectroscopic methods as well as through comparisons made with data reported in the literature. Some isolated compounds were evaluated for their antioxidant, α-glucosidase inhibitory and cytotoxic activities. Compound 4, 6 and 7 showed significant antioxidant activity against DPPH radicals with IC50 values ranging from 7.45–16.12 μM. Compound 4 also exhibited potent activity against ABTS•+ scavenging activity with an IC50 value of 0.55 ± 0.01 μM which was better than positive control (ascorbic acid, IC50 2.35 ± 0.17 μM). Compound 12 showed significant α-glucosidase inhibitory activity with an IC50 value of 0.02 ± 0.37 mM. Compounds 5, 6 and 12 showed weak cytotoxic activities against a colon cancer cell line with IC50 values ranging from 22.35–47.62 μM.