The objective of this research was to investigate the anti-inflammatory effect of mahkota dewa (Phaleria macrocarpa) fruit pericarp extract on COX-2 and β-catenin expression in mice colon induced by dextran sodium sulphate (DSS). The anti-inflammatory activity was performed by DSS-induced colitis model through assessment of COX-2 and β-catenin expression by immunohistochemistry assay at four different doses, i.e. 650 mg/kg, 1250 mg/kg, 2500 mg/kg and 5000 mg/kg. Swiss webster male mice weighing 25-30 g were used for the study. The results of COX-2 optical density score in dose 625 mg/kg, 1250 mg/kg, 2500 mg/kg and 5000 mg/kg were 1.58, 1.52, 1.47, 1.33, respectively. This result was significantly different (p = 0.000) with DSS group that was 2.46 Meanwhile β-catenin optical density score in dose 625 mg/kg, 1250 mg/kg, 2500 mg/kg and 5000 mg/kg were 1.46, 1.37, 1.41, 1.36, respectively. This result was significantly different (p = 0.000) with DSS group that was 2.34. Pericarp extract of P. macrocarpa fruit exhibited anti-inflammatory activity in experimental model shown by suppressing expression of COX-2 and β-catenin.