<p>Negative pressure wound therapy (NPWT) has been shown to be beneficial for improving the wound healing process and reducing flap complications. However, the ideal NPWT settings, especially the pressure levels and application modes, are still debatable. This study examines the efficacy and safety of NPWT at different pressure gradients, namely, high (HNPWT) and low (LNPWT), to determine the optimal conditions for improving flap outcomes and minimizing complications. Over a 30-month period, 65 patients who underwent flap reconstruction were randomly assigned to three groups: HNPWT (75–125&#xa0;mmHg, continuous mode), LNPWT (50–75 mmHg, intermittent mode), and conventional wound dressing (CWD). Patients were evaluated prospectively for post-operative complications, flap viability, infection, edema, and wound dehiscence. Complications were more common in the CWD group than in the HNPWT group, while the HNPWT group &#xa0;had the highest incidence of flap ischemia (41%). NPWT significantly reduced post-operative edema (<i>P</i> = 0.003) and&#xa0;lower infection and dehiscence rates than the CWD group (<i>P</i> = 0.015 and <i>P</i> = 0.029, respectively). Compared with HNPWT, LNPWT showed superior safety and efficacy, with fewer ischemic events, lower pain scores, faster wound healing times, and better esthetic and function outcomes. Although NPWT offers benefits over conventional wound dressing in flap reconstructions, pressure settings should be carefully adjusted. LNPWT is safer and has more satisfactory outcomes than HNPWT, with reduced ischemia and better overall healing. These findings suggest that LNPWT in the intermittent mode is most favorable for improving flap viability and minimizing adverse effects.</p><p><i>Registration identification number</i> NCT06080958- July 22, 2024. “Retrospectively registered” URL for the registry: <a href="http://www.clinicaltrials.gov/">http://www.clinicaltrials.gov/</a></p>