Objective To explore the effect and mechanism of human umbilical cord mesenchymal stem cell (hucMSC)-derived exosome (hucMSC-Exo) on wound healing of stage 4 pressure ulcers in mice. Methods hucMSCs were isolated and cultured in primary culture. hucMSC-Exos were extracted from the supernatant of hucMSCs at passage 5 (P5) through differential centrifugation. Twenty-seven BALB/c mice with stage 4 pressure ulcers were randomly divided into hucMSC-Exo group (injected subcutaneously with 100 μg hucMSC-Exo dissolved in 100 μL phosphate-buffered saline[PBS]), PBS group (injected subcutaneously with 100 μL PBS), and model group (without injection of hucMSC-Exo or PBS). The wound healing of pressure ulcers was assessed after treatment, and the wound healing rate was estimated on day 0, 3, 7, 10, and 14. Hematoxylin-eosin (H-E) staining and Masson staining were used to observe the pathological changes of the wound on day 7 and 14 after treatment. The expression of α-smooth muscle actin (α-SMA) protein related to scar formation was detected by immunohistochemical staining with skin samples on day 7 after treatment. Serum samples were obtained on day 7 and 14 after treatment to detect the dynamic changes of superoxide dismutase (SOD) activity and malondialdehyde (MDA) content. Results Compared with the PBS and model groups, the hucMSC-Exo group had much shorter wound healing time, less scar formation, and higher wound healing rate. Histopathology examination showed that, compared with the PBS and model groups, the wound injury and inflammatory infiltration in the hucMSC-Exo group were significantly decreased, collagen deposition was greatly boosted, and collagen fibers were orderly arranged and distributed. Immunohistochemical staining showed that the expression of α-SMA protein in the hucMSC-Exo group was lower than those in the PBS and model groups. The results of serum biochemical test showed that SOD activity in the hucMSC-Exo group was higher than those in the PBS and model groups (both P<0.05) on day 7 after treatment, approaching the normal level on day 14; MDA content was lower in the hucMSC-Exo group than the PBS and model groups on day 7 and 14 (all P<0.05). Conclusion Subcutaneous injection of hucMSC-Exo can promote wound healing and minimize scar formation in mice with stage 4 pressure ulcers. The mechanism may be related to the improvement of in vivo oxidative stress levels by hucMSC-Exo.