Breast cancer, irrespective of gender, stands as the most prevalent cancer globally, with an annual estimate of 2.3 million new cases. Surgical intervention, including therapeutic mastectomy (excluding prophylactic procedures), is performed on approximately 28% of patients, necessitating subsequent breast reconstruction. Although implant-based breast reconstruction (IBBR) is frequently employed due to its relative ease compared to autologous methods, it presents a notable risk for complications at mid-term such as peri-prosthetic infections. These complications can lead to implant loss and the eventual compromise of the mastectomy pocket. To address these complications, negative pressure wound therapy with instillation and dwell (NPWTi-d) emerges as a promising rescue intervention, known for its capacity to significantly reduce bacterial load and potentially salvage compromised soft tissues. However, the evidence supporting its effectiveness in infected pockets after mastectomy is currently insufficient. This study aims at investigating the efficacy of NPWTi-d in the management of peri-prosthetic mastectomy pocket infection. A thorough literature search has been concluded through PubMed, Web of Science, and Cochrane databases up until 18th March 2025 on evaluating NPWTi-d's ability to manage peri-prosthetic infections and preserve mastectomy pockets for subsequent reconstruction. Furthermore, a meta-analysis on the salvage rate of the mastectomy pocket was carried out, while for other outcomes, a descriptive analysis was applied. Nine studies (n = 230 patients) were included, investigating whether the us NPWTi-d was successful in treating peri-prosthetic infection and preserving the mastectomy pocket for subsequent reconstruction by expander or implant. The pooled salvage rate of the implant-based BR due to the use of NPWTi-d was 86.1% (95%CI: 80.6-91.6%). Preservation of the skin envelope avoided secondary reconstruction after a defined time interval, reducing number and complexity of surgeries and related costs. This innovative surgical approach should be considered in selected cases of infected implants after breast reconstruction in breast cancer centers. However, the actual low level of evidence is based on case series, and it is not possible to define generally accepted recommendations for the use of NPWTi-d to save the mastectomy pocket.