Background To explore the efficacy, safety, and cost implications of NPWT versus standard wound care (SWC) for Diabetic Foot Ulcers (DFUs). Methods 91 patients with DFUs were included in this retrospective study from May 2017 and February 2024. All patients were divided into NPWT (n = 44) and SWC (n = 47) groups based on the surgery methods. Arterial disease severity was assessed via ankle-brachial index (ABI) and Doppler ultrasound, with subgroups categorized as severe ischemia (ABI < 0.4), moderate ischemia (ABI 0.4-0.7), and normal/mild ischemia (ABI > 0.7). Baseline characteristics, wound parameters, healing progression, adverse events, costs, and subgroup outcomes by arterial disease status were compared between two groups. Results At the 4-week assessment, the NPWT group exhibited significantly higher mean percentage reduction in wound area (35.01% vs. 32.53%, P = 0.033) and greater reduction in wound depth (2.74 mm vs. 2.14 mm, P = 0.032) compared to the SWC group. A notably higher proportion of NPWT patients achieved complete wound closure (52.27% vs. 27.66%, P = 0.029), resolution of infection (88.64% vs. 68.09%, P = 0.035), and neuropathy improvement (59.09% vs. 34.04%, P = 0.029). NPWT also showed lower wound infection rates (9.09% vs. 29.79%, P = 0.027) but higher skin irritation (31.82% vs. 10.64%, P = 0.026). Subgroup analysis revealed NPWT's superiority in both PAD-positive (48.0% vs. 20.0%, RR = 2.40, 95% CI: 1.12-5.15, P = 0.042) and PAD-negative subgroups (55.2% vs. 30.4%, RR = 1.82, 95% CI: 1.05-3.15, P = 0.031). Even in severe ischemia (ABI < 0.4), NPWT achieved higher closure rates (36.4% vs. 12.5%, P = 0.038). While total treatment costs were comparable (P = 0.084), NPWT reduced hospitalization days (16.05 vs. 21.38 days, P = 0.028) and drug costs (5229.33 RMB vs. 5915.5 RMB, P = 0.030). Conclusion NPWT is more superior in safety, cost-efficiency, and long-term wound management compared to SWC. Trial registrationNot applicable.