Background Surgical site infections (SSIs) in spinal surgery are a severe complication with a considerable impact on patient quality of life and healthcare costs. Despite the established efficacy of negative pressure wound therapy (NPWT) in preventing surgical wound complications, there is a lack of strong evidence supporting its use in spinal surgery. The objective of this research is to assess the efficacy and economic impact of prophylactic NPWT using PICO-7 dressings in preventing SSIs after posterior lumbar fusion. Methods A retrospective matched case-control study was conducted, including 100 adult patients who underwent 1- or 2-level instrumented posterior lumbar fusion for degenerative spinal stenosis between 2020 and 2023. Fifty patients received PICO-7 dressings, while 50 matched controls received conventional compressive dressings. Demographic, perioperative, and postoperative variables were analyzed. SSI was defined by clinical signs, laboratory markers, and positive intraoperative cultures. A cost-benefit analysis was performed from the hospital perspective. Results The incidence of SSI was significantly lower in the PICO-7 group compared to controls (4% vs 18%; OR = 0.19; 95% CI: 0.03–0.92). NPWT was also associated with reduced rates of wound dehiscence (0% vs 6%; P = 0.08) and hospital readmission (0% vs 10%; OR = 0.08; 95% CI: 0.04–0.92), as well as a shorter median length of stay (4 vs 4.5 days; P = 0.04). Greater intraoperative blood loss was independently associated with increased SSI risk (d = 0.39; 95% CI: −1.5 to −0.08) but did not modify the protective effect of PICO-7. The cost-benefit analysis showed a net savings of $171,545 and a cost-benefit ratio of 4.21. Sensitivity analysis confirmed the robustness of these findings. Conclusion Prophylactic use of PICO-7 dressings significantly reduces SSI incidence and associated morbidity in posterior lumbar fusion with substantial economic benefits. These results support the integration of NPWT into standard postoperative wound management protocols for selected spinal procedures. Clinical Relevance This study offers a comprehensive set of clinical and economic data that serves as a valuable foundation for the development of prospective studies on the standardized implementation of NPWT in wound management in spinal surgery. Level of Evidence 3b.