Closed incision negative pressure therapy (ciNPT) system use compared with standard of care dressings (SOC) on surgical site infection (SSI) in cardiac surgery was assessed. A systematic literature review was conducted. Risk ratios (RR) and random effects models were used to assess ciNPT with foam dressing (ciNPT-F) or multilayer absorbent dressing (ciNPT-MLA) versus SOC. Health economic models were developed to assess potential per patient cost savings. Eight studies were included in the ciNPT-F analysis and four studies were included in the ciNPT-MLA analysis. For ciNPT-F, a significant reduction in SSI incidence was observed (RR: 0.507, 95% confidence interval [CI]: 0.362, 0.709; p < 0.001). High-risk study analysis reported significant SSI reduction with ciNPT-F use (RR: 0.390, 95% CI: 0.205, 0.741; p = 0.004). For ciNPT-MLA, no significant difference in SSI rates were reported (RR: 0.672, 95% CI: 0.276, 1.635; p = 0.381). Health economic modelling estimated a per patient cost savings of $554 for all patients and $3242 for the high-risk population with ciNPT-F use. Health economic modelling suggests ciNPT-F may provide a cost-effective solution for sternotomy incision management. However, limited high-quality literature exists. More high-quality evidence is needed to fully assess the impact of ciNPT use following cardiac surgery.