Phytochemical investigation of Maclura fruticosa (Moraceae) yielded twelve flavonoids from its twigs and leaves, including six undescribed compounds: five prenylated isoflavones (maccosas G-K, 1-5) and one benzylated dihydroflavonol (maccosa L, 6), alongside six known analogues (7-12). Structural elucidation was accomplished through NMR, HRESIMS, and ECD analyses. The anti-inflammatory activity of all the isolated compounds was screened and three benzylated dihydroflavonols (6, 11 and 12) exhibited potent anti-inflammatory activities. Compound 6 decreased LDH level in a dose-dependent manner, showing IC50 value of 8.53 μM.