Atmospheric pressure plasma jet (APPJ) were used to decontaminate the surface’s 2-Chloroethyl ethyl sulfide (2-CEES), a kind of sulfur mustard (HD) simulant. The power of the APPJ device didn’t exceed 7.77 W. Helium APPJ was easier to generate plasma jet than argon APPJ. The treated nude mouse skin surface’s temperature slowly reached 30.4 °C and no obvious lesions in the dermis and skin appendages after 15 min treatment. Compared with argon APPJ, the helium APPJ produced more ·OH and the maximum concentration of ·OH was 3.748 × 10−9 mol/L. Attributed to the low density and more ·OH content, the helium APPJ had a better decontamination effect. With a maximum voltage of 7 kV and a helium flow rate of 4 L/min, 2-CEES (4.53 mg/cm2) can be completely decontaminated in 2.5 min, and no gaseous 2-CEES was detected. The detection of the 2-Hydroxyethyl ethyl sulfide proved the role of ·OH in the reaction system. During the reaction, 2-Chloroethyl ethyl sulfoxide and 2-Chloroethyl ethyl sulfone were also detected. The plasma jet could reduce the toxicity by destroying the parent molecule (2-CEES) in a short time, but it took more time to eliminate the intermediate products. No relevant intermediate products were detected in the gaseous, ensured the safety of personnel operating in open spaces.