Negative pressure wound therapy (NPWT) is associated with improved outcomes in complex wound healing and unclear clinical-economic differentiation among NPWT devices based on a recent study. The objective of this study was to estimate the cost of care associated with two NPWT technologies for patients admitted to the hospital with moderate to severe foot infections. A decision tree simulation model was developed to estimate the hospital costs associated of two different NPWT technologies: Cardinal Health™ PRO (NPWT-C); V.A.C. Ulta™ (NPWT-K). Clinical data were obtained from a previously completed single-site prospective comparative trial. The primary outcome of this trial was the proportion healed at 12-weeks, and secondary outcomes included adverse events and healthcare utilization. Cost data were obtained from a best evidence literature review and inflated to 2018 United States Dollars. One-way and probabilistic sensitivity analyses were performed to gauge the robustness of the results. The trial randomized 60 patients equally to the NWPT-C and NPWT-K and found similar rates of wound healing of 50.0% and 46.7% (p = 0.39). Secondary outcomes including adverse events, and healthcare utilization during the treatment course were similar. However, the total expected per-patient costs were $41,206 (SD $8,194) and $44,439 (SD $8,963) for NPWT-C and NPWT-K, respectively. The minimum expected per-patient cost was $20,036 for NPWT-C and $20,876 for NPWT-K. The maximum expected per-patient cost was $67,460 for NPWT-C and $74,103 for NPWT-K. One-way sensitivity analyses revealed that the model was most sensitive to hospital length-of-stay. Probabilistic sensitivity analysis revealed that NPWT-C was expected to be the cost minimizing technology in 74% of model iterations. NPWT-C was expected to be the cost minimizing NPWT technology over the course of treatment with an average expected savings of $3,233 per-patient. Larger studies are recommended to confirm these findings.