Extracellular superoxide dismutase (EC‐SOD) is an enzyme that catalyses the dismutation of superoxide anions. It has multiple functions, such as reactive oxygen species scavenging, anti‐angiogenic, anti‐inflammatory, antichemotatic and antitumor activities. Recently, we demonstrated that EC‐SOD inhibits ovalbumin‐induced allergic airway inflammation in mice. However, the anti‐allergic effect of EC‐SOD on skin tissue and the role of EC‐SOD in mast cells, which are important for allergic responses, have not been well studied. In this study, we investigated whether EC‐SOD can alleviate atopic dermatitis in mice and inhibit mast cell activation. Treatment with human recombinant EC‐SOD ameliorated house dust mite‐induced atopic dermatitis in mice. Furthermore, the levels of pro‐allergic cytokine gene expression and histamine release increased in EC‐SOD KO mast cells and decreased in EC‐SOD overexpressing mast cells, suggesting that EC‐SOD inhibits mast cell activation. Consistently, a passive cutaneous anaphylaxis experiment showed more blood leakage from EC‐SOD KO mouse ear skin, implying that the lack of EC‐SOD increases allergic responses. These results suggest that EC‐SOD inhibits mast cell activation and atopic dermatitis and that the loss of EC‐SOD causes more severe allergic responses, implying that EC‐SOD might be a good drug candidate for treatment of allergic disorders, such as atopic dermatitis.