Dracontomelon dao (D. dao) is the leaves of Dracontomelon duperreanum Pierre (D. dao auct. non (Blanco) Merr. and Rolfe; D. sinense Stopf.). As a valuable traditional Chinese medicine from Anacardiaceae, D. dao has a long history of treating bedsores, skin ulcers, and other infection diseases. In addition, the volatile oil from D. dao leaves exhibits antitumor effects. However, these reported studies only focused on evaluating the antimicrobial efficacy on model strains in vitro, without paying attention to the antimicrobial activity and anti-inflammatory effects in vivo. This study was aimed to provide evidence of antimicrobial activity and anti-inflammatory and proangiogenesis activities of Dracontomelon dao (D. dao) on the skin of rats under simulated space environment. The weightlessness model of rats in space environment was established. Then, rats were given D. dao for 15 days. Wound healing effects of D. dao on histopathology and inflammatory cytokines in E. coli-induced wound infection in weightless rats were analyzed. Furthermore, the molecular biology technology was performed to evaluate the wound healing effects of D. dao on the relative protein level of NF-κB as well as PI3K/Akt signaling pathways. Immunohistochemistry was used for the protein expression of VEGFA. The wound healing effects of D. dao on bacterially infected wounds in rats were manifested by lowering the size of the wound and significantly increasing the shrinkage rate of the wound. D. dao had effect on alleviating histological damage of skin tissue and downregulation inflammatory cytokines level. In addition, the results indicated that D. dao has a regulatory effect on inflammation and angiogenesis and could regulate the relative protein level of MAPK/NF-κB as well as PI3K/AKT signaling pathways. The current study highlighted the crucial role of D. dao in relieving skin tissue injury in E. coli-induced wound infection in weightless rats by regulating the MAPK/NF-κB as well as PI3K/AKT signaling pathways. This study could provide a new agent for the treatment of bacterial infected wounds in simulated space environment.