Background: High purity oxygen therapy has good clinical efficacy in the treatment of diabetic foot (DF), but its mechanism of promoting wound healing has been unclear.Methods: Patients with DF were randomly divided into an experimental group and a control group. The experimental group was given local oxygen therapy (LOT) by a micro-oxygen therapy instrument, which administered uninterrupted >95% pure oxygen for 24 h at a flow rate of 3 mL/h. Six skin samples from the experimental group before and after treatment underwent RNA sequencing (RNA-seq), and the differentially expressed genes (DEGs) were screened. Results:The clinical results showed that the mean wound healing time of the experimental group was 26 days (P<0.05); the healing area of the experimental group was 3.1-15.3 cm 3 , with a mean of 8.8 cm 3 , and that of the control group was 2.4-10.4 cm 3 (P<0.05). LOT promoted the healing of DF wounds mainly through the tumor necrosis factor (TNF) signaling pathway and the apoptosis pathway.Conclusions: According to our results, LOT can promote DF healing mainly by inhibiting the local oxidative stress reaction of wound skin and by inhibiting the inflammatory and apoptotic pathways. The molecular markers and pathways screened warrant further study.