This study was conducted to investigate the antioxidative and anti-inflammatory effects of watermelon lycopene. The antioxidant activities of watermelon were measured using various assays including the evaluation of 1,1-diphenyl-2-picrylhydrazyl (DPPH) radical scavenging activities, superoxide anion scavenging activities and ferric reducing antioxidant power (FRAP) assay, compared with those of tomato lycopene and Trolox as a positive control. Watermelon lycopene showed significantly higher antioxidant activities than those of tomato lycopene and comparable superoxide anion scavenging activity to that of Trolox. Furthermore, the protein and mRNA levels of inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2) in lipopolysaccharide (LPS)-stimulated HaCaT cells were investigated by Western blotting and reverse transcription–polymerase chain reaction. Watermelon lycopene dose dependently inhibited the expressions of iNOS and COX-2 mRNA levels and their proteins, suggesting that watermelon lycopene has strong anti-inflammatory activity. Consequently, the watermelon lycopene was proved as a good source of antioxidant and anti-inflammatory agent.