Wounds are in a stressed state, which precludes healing. Trehalose is a stress metabolite that protects cells under stress. Here, we explored whether trehalose reduces stress-induced wound tissue damage. A stress model was prepared by exposing human keratinocytes to hydrogen peroxide (HO), followed by trehalose treatment. Trehalose effects on expression of the autophagy-related proteins ATG5 and ATG7 and cell proliferation and migration were evaluated. For in vivo verification, a wound model was established in Sprague-Dawley rats, to measure the effects of trehalose wound-healing rate and reactive oxygen species (ROS) content. Histological changes during wound healing and trehalose's effects on ATG5 and ATG7 expression, necrosis, and apoptosis were examined·HO stress increased ATG5 and ATG7 expression in vitro, but this was insufficient to prevent stress-induced damage. Trehalose further increased ATG5/ATG7 levels, which restored proliferation and increased migration by depolymerizing the cytoskeleton. However, trehalose did not exert these effects after ATG5 and ATG7 knockout. In vivo, the ROS content was higher in the wound tissue than in normal skin. Trehalose increased ATG5/ATG7 expression in wound tissue keratinocytes, reduced necrosis, depolymerized the cytoskeleton, and promoted cell migration, thereby promoting wound healing.