Background: Flavonoids are groups of natural phytonutrients found in fruits and vegetables that have recently become popular because of their anti-oxidation and anti-inflammatory ability. Narirutin is a flavanone which has been proven to have anti-inflammation effects, although its fundamental mechanisms are not understood. Objective: We try to investigate this anti-inflammatory effect of narirutin in human monocytic THP-1-derived M1 macrophage cells. Materials and Methods: To confirm our hypothesis, human THP-1 cells (1 × 106 cells/mL) were initially treated with 20 ng/mL phorbol 12-myristate 13-acetate (PMA) for 24 h. The PMA-differentiated THP-1 cells were treated with various levels of narirutin 2 h before lipopolysaccharide stimulation; after that, the cells were cultured for 24–48 h and then examined. The concentration of interferon-gamma-inducible protein-10 (IP-10) was measured using enzyme-linked immunosorbent assay. Epigenetic regulation mechanisms were explored by chromatin immunoprecipitation assay. Results: Narirutin significantly suppressed IP-10 production in M1 macrophage cells, and the suppressing effect was partly reversed by the estrogen receptor antagonist, the aryl-hydrocarbon receptor antagonist, the peroxisome proliferator-activated receptor (PPAR)-α antagonist, and the PPAR-γ antagonist. We also found that narirutin-induced IP-10 suppression can be modulated by both histone H3 and H4 acetylation. Conclusion: Our study suggests the potential of narirutin for the treatment of inflammatory disease by suppressing IP-10.