Allergies have become a global problem, and effective control is greatly needed. Here, the inactivation effects of the atmospheric pressure cold plasma (APCP) on aerosolized allergens including Der p 1, Der f 1, Asp f 1, Alt a 1, and Can f 1 as well as those from indoor and outdoor environments were investigated. The effectiveness of the APCP treatment was further studied using blood sera from the allergen sensitized humans. In addition, the allergen samples were also analyzed using sodium dodecyl sulfate polyacrylamide gel electrophoresis (SDS-PAGE). Results revealed that the APCP was highly effective in reducing the allergenicity of both lab-prepared and environmental allergen aerosols. The airborne reductions were shown to range from 30% for Der p 1 to 80% for Can f 1 allergen for 0.12 s exposure. Allergnicity tests showed that the APCP treated Asp f 1 allergens caused 50% less binding with IgEs in the blood sera compared to the control. The observed allergenicity loss was due to hydroxyl radicals produced by the plasma device. The results from SDS-PAGE showed that the plasma treatment resulted in decreased size of the Asp f 1 allergen. The developed technology holds great promise in combating the allergic diseases.