Plastic surgery frequently employs random skin flaps. However, its clinical applicability is constrained by flap necrosis brought on by ischemia–reperfusion damage. Flap survival is aided by rosuvastatin, a naturally occurring flavonoid primarily obtained from plants. In this research, we looked into the processes mediating the effects of rosuvastatin on flap survival. All experimental mice were randomly assigned to three groups: control, rosuvastatin, and 3-methyladenine (3MA) plus rosuvastatin. These groups were, respectively, treated with dimethyl sulfoxide solution, rosuvastatin, and rosuvastatin combined with 3MA. After that, the animals were euthanized so that histology and protein analyses could determine the extent of angiogenesis, pyroptosis, oxidative stress, and autophagy. In addition to lessening tissue edema, rosuvastatin promoted the survival of the skin flap. Rosuvastatin also promoted angiogenesis, reduced oxidative stress, induced autophagy, and reduced pyroptosis. According to the study's findings, rosuvastatin increases angiogenesis, prevents pyroptosis, and reduces oxidative stress by inducing autophagy, which improves the survival rate of random skin flaps.