Background and Purpose: Caffeic acid phenethyl ester (CAPE), a phenolic compound isolated from propolis, displays a variety of biological activities. The aim is to examine the protective effect and mechanisms of CAPE on an eccentric exercise-induced muscle injury model. Experimental Approach: An intermittent downhill eccentric exercise protocol was used. The oxidative tissue injury and expression of cyclooxygenase-2 (COX-2), inducible nitric oxide synthase (iNOS), interleukin-1β (IL-1β), monocyte chemotactic protein-1 (MCP-1), and activation of nuclear factor-κB (NF-κB) were examined. CAPE was applied in a dose of 5 and 10 mg/kg/day, p.o. Key Results: The eccentric exercise induced remarkable skeletal muscle damage uncovered by a dramatic elevation of creatine kinase in the serum and severe degenerative myopathy. These pathophysiological changes were accompanied by an upregulation of the inflammatory responses including protein nitrotyrosylation, poly-ADP-ribose-polymerase (PARP) upregulation, lipid peroxidation as measured by malondialdehyde (MDA) formation, and leukocyte infiltration as measured by myeloperoxidase (MPO). The inflammatory responses primarily resulted from enhanced expression of COX2, iNOS, and production of IL-1β and MCP-1, possibly through activation of NF-κB. All these pathological changes were suppressed by treatment of CAPE. Conclusions and Implications: Our results indicate that CAPE exhibits protective effects against eccentric exercise-induced skeletal muscle damage in rats by blocking the NF-κB-dependent activation of the inflammatory responses.