Background: Negative pressure wound therapy (NPWT) is traditionally used to treat postoperative wound infections. However, its use in closed wound sternotomy post cardiac surgery in high-risk patients has become increasingly popular. The potential preventive benefit of reducing sternal wound infections has been recently acknowledged. Bilateral internal mammary artery (BIMA) grafts are used in coronary artery bypass grafting but have been associated with an increased risk of sternal wound infections (SWIs). Objectives: This systematic analysis examines whether NPWT can reduce the incidence of SWI following BIMA grafts, leading to more patients benefiting from the better survival outcome associated with BIMA grafting. Method: A comprehensive systematic search and meta-analysis were performed to identify studies on the use of NPWT in closed wound sternotomy. Ovid MEDLINE (in-process and other nonindexed citations and Ovid MEDLINE 1990 to present), Ovid EMBASE (1990 to present), and The Cochrane Library (Wiley), PubMed, and Google Scholar databases were searched from their inception to May 2022 using keywords and MeSH terms. Thirty-four articles from 1991 to May 2022 were selected. Result: Three studies reported on the outcome of NPWT following BIMA grafting. The pooled analysis did not show any significant difference in the incidence of sternal wound infection between NPWT and standard dressing (RR 0.48 95% CI 0.17–1.37; P = 0.17) with substantial heterogeneity (I2 65%). Another seven studies were found comparing the outcome of SWI incidence of negative pressure closed wound therapy with conventional wound therapy in patients undergoing adult cardiac surgery. The pooled analysis showed that NPWT was associated with a low risk of SWIs compared to conventional dressing (RR 0.47 95% CI 0.36–0.59; P < 0.00001), with low heterogeneity (I2 1%). Conclusion: The literature identified that NPWT significantly decreased the incidence of sternal wound complications when applied to sutured sternotomy incisions in high-risk patients, and in some cases, it eliminated the risk. However, the inadequate number of randomized controlled trials assessing the effectiveness of NPWT in BIMA grafting emphasizes the need for further, robust studies.