Our objective was to estimate the US national cost burden of hospital‐acquired pressure injury (HAPI) using economic simulation methods. We created a Markov simulation to estimate costs for staged pressure injuries acquired during hospitalisation from the hospital perspective. The model analysed outcomes of hospitalised adults with acute illness in 1‐day cycles until all patients were terminated at the point of discharge or death. Simulations that developed a staged pressure injury after 4 days could advance from Stages 1 to 4 and accrue additional costs for Stages 3 and 4. We measured costs in 2016 US dollars representing the total cost of acute care attributable to HAPI incidence at the patient level and for the entire United States based on the previously reported epidemiology of pressure injury. US HAPI costs could exceed $26.8 billion. About 59% of these costs are disproportionately attributable to a small rate of Stages 3 and 4 full‐thickness wounds, which occupy clinician time and hospital resources. HAPIs remain a concern with regard to hospital quality in addition to being a major source of economic burden on the US health care system. Hospitals should invest more in quality improvement of early detection and care for pressure injury to avoid higher costs.