In this study, polyphenols from Durian hull were extracted by 80% methanol, and their antioxidant and anti-inflammatory activities were investigated based on in vitro antioxidant assays and LPS-stimulated RAW 264.7 cells model. The results demonstrated that durian hull extract was rich in polyphenols, it showed strong antioxidant activity in vitro and it could reduce the expression level of inducible nitricoxide synthase (iNOS) and cyclooxygenase-2 (COX-2), decrease the NO production, and also lower the pro-inflammatory cytokines (TNF-α, IL-1β and IL-6) at the mRNA and protein levels. At the same time, it can inhibit the phosphorylation of IκB and p65 proteins related to the NF-κB signaling pathway and inhibit the expression of NF-κB, thereby reducing inflammatory damages.