Telmesteine, a useful agent for respiratory tract disorders, has been reported to be a critical active ingredient in topical compositions for dermatitis. The present study was designed to elucidate the in vitro and in vivo anti-inflammatory properties of telmesteine. LPS-induced NO production in RAW264.7 cells was significantly decreased after telmesteine treatment. TPA-induced skin inflammation as assessed by skin edema and pro-inflammatory cytokines (IL-1β, IL-6, and TNF-α) was significantly decreased after telmesteine topical treatment. Further analysis results demonstrated that the anti-inflammation properties of telmesteine were associated with its ability to inhibit activation of nuclear factor kappa-κB (NF-κB) by blocking phosphoinositide 3-kinase/protein kinase B (PI3K/Akt)/IκB kinase (IKK) activities.