Background <p>Diabetic foot ulcer (DFU) is one of the most common complications in diabetic patients. In recent years, vacuum sealing drainage (VSD) therapy has been widely applied in clinical wound healing, effectively promoting wound healing and reducing the occurrence of infections. However, VSD therapy can only locally improve the wound microenvironment and is insufficient in regulating systemic inflammatory responses. Alprostadil, a prostaglandin, has shown certain effectiveness in the treatment of DFU by improving microcirculation and promoting blood flow. Lipoic acid, a potent antioxidant, can alleviate oxidative stress, improve metabolic abnormalities, and reduce inflammatory responses in diabetic patients, thereby promoting wound healing. The combined use of VSD, alprostadil, and lipoic acid may have a synergistic effect in the treatment of DFU.</p> Objective <p>This study conducts a retrospective analysis of clinical data from diabetic foot ulcer (DFU) patients treated at our institution to investigate the therapeutic efficacy of vacuum sealing drainage (VSD) combined with alprostadil and lipoic acid in treating DFUs, and its impact on inflammatory factors in patients.</p> Methods <p>A retrospective analysis was conducted on the clinical data of 98 patients diagnosed with DFU who were admitted to our hospital between January 2022 and February 2023. Based on their respective treatment protocols, the patients were categorized into two groups: the control group (<i>n</i> = 52) and the observation group (<i>n</i> = 46). All patients enrolled in the study underwent VSD treatment, with the observation group receiving additional alprostadil and lipoic acid supplementation. The therapeutic efficacy was evaluated for all participants 2&#xa0;weeks after treatment initiation, and the wound healing time, the time of stopping using VSD and its hospitalization time, hospitalization expenses, and adverse reactions of the two groups were recorded. Furthermore, analyses included pre- and post-treatment assessments of growth factor levels in granulation tissue, alongside evaluations of fibrotic activity markers, oxidative stress indicators, inflammatory cytokine profiles, and arterial hemodynamics in both groups. Results.</p> Results <p>The observation group demonstrated a significantly higher effective rate of 93.48% (43/46) compared to 76.92% (40/52) in the control group, and the wound healing time of observer was lower than that of control group (<i>p</i> &lt; 0.05). Post-treatment, levels of VEGF and PDGF in granulation tissue increased in both groups relative to pre-treatment levels, with higher levels observed in the observation group compared to the control group (<i>p</i> &lt; 0.05). Post-treatment, levels of tPA, SOD, GSH-PX, CAT, blood flow velocity, vessel inner diameter, RI, and PI in both groups were higher than pre-treatment levels, while levels of FPA, PAI-1, CRP, IL-6, Hcy, and TNF-α were lower than pre-treatment levels. Additionally, the observation group exhibited higher levels of tPA, SOD, GSH-PX, CAT, blood flow velocity, vessel inner diameter, RI, and PI compared to the control group and lower levels of FPA, PAI-1, CRP, IL-6, Hcy, and TNF-α compared to the control group (<i>p</i> &lt; 0.05). The time to stop using VSD, hospitalization time, and hospitalization expenses in the observation group was lower than those in the control group (<i>p</i> &lt; 0.05).</p> Conclusion <p>The treatment of DFU with VSD combined with alprostadil and lipoic acid can significantly promote wound healing and granulation growth, shorten wound healing time, effectively enhance cellulase activity and antioxidant capacity of patients, relieve inflammation, and protect vascular endothelial cells, with high efficiency and safety, and effectively reduce the use time of VSD and the hospitalization time and expenses of patients, which is worthy of promotion.&#xa0;</p>