Cold atmospheric plasma (CAP) has been reported as a novel potential way to promote skin wound healing. The aim of this study was to explore the effects of an atmospheric-pressure plasma generated in helium gas through dielectric barrier discharge on skin wound healing in rats and its mechanism. A total of 44 adult male Sprague-Dawley rats were divided into the CAP group and the control group after a full-thickness skin wound model was established. The animals in the CAP group received CAP treatment (driving frequency 17 kHz, root-mean-square [rms] values of the discharge voltage 1.33 kV, rms values of the discharge current 10.7 mA, helium flow rate 11 slpm [standard litres per minute]) for 1 min. After that, the size of the healed area of the wound, morphological changes in the wound, wound neovascularization, collagen deposition, and the level of inflammatory factors were recorded. The results showed that compared to that of the control group, the size of the wound area in the CAP group significantly decreased, the contraction and re-epithelialization of the wounds were obviously speeded up, and the protein level of smooth muscle actin markedly increased. However, the levels of collagen type I A2, collagen type III, and the deposition of collagen bundles did not change. In addition, it was found that the level of inflammatory factors (such as tumour necrosis factor and interleukin-1 ) significantly increased at 24 hr after the creation of the wound. These results suggest that CAP treatment in this condition could promote skin wound healing by accelerating the contraction, re-epithelialization, neovascularization, and inflammatory response.