Background: Pain after traumatic injury is common, yet few patients receive adequate pain relief. NHS paramedics have a limited formulary to treat severe pain. Objectives: To estimate the cost-effectiveness of ketamine versus morphine for severe pain in acute traumatic injury. Methods: A cost-utility analysis was conducted based on data from a pragmatic, multicentre, randomised controlled trial (PACKMAN). The base-case analysis took the form of an intention-to-treat analysis conducted from a UK National Health Service (NHS) and personal social services (PSS) perspective and separately from a societal perspective. Costs (£ 2021–2022 prices) were collected prospectively over a 6-month follow-up period. A bivariate regression of costs and quality-adjusted life-years (QALYs), with multiple imputation of missing data, was conducted to estimate the incremental cost per QALY gained and the incremental net monetary benefit (INMB) of ketamine in comparison to morphine. Sensitivity and pre-specified subgroup analyses explored uncertainty and heterogeneity in cost-effectiveness estimates. Results: Participants (n = 416) were randomised to ketamine (n = 206) or morphine (n = 210) amongst whom complete data for the economic evaluation was available for 189 (45.4%) participants. Mean (standard deviation [SD]) observed NHS and PSS costs over 6 months were £5,191 (£3,155) in the ketamine arm versus £5,143 (£3,897) in the morphine arm (mean difference [MD]: £47). Mean (SD) observed QALY estimates were 0.309 (0.10) versus 0.293 (0.010), respectively (MD: 0.016). The base case (imputed) analysis generated an incremental cost of -£117 (95%CI: -£849 to £597) and incremental QALYs of 0.025 (95%CI: 0.010 to 0.041), indicating a 92%-96% probability of cost-effectiveness at cost-effectiveness thresholds of £20,000 and £30,000 per QALY. A sensitivity analysis, using observed data only (without imputation) generated an incremental cost of £233 (95%CI: -£783 to £1216) and incremental QALYs of 0.016 (95%CI: -0.013 to 0.044), indicating a lower 54%-62% probability of cost-effectiveness. The base-case cost-effectiveness results remained robust to other sensitivity analyses. Conclusions: This economic evaluation found that ketamine administered by paramedics to adults with severe pain following traumatic injuries is cost-effective compared to morphine. However, our results are subject to high levels of missing data, which were handled through recommended multiple imputation techniques. Trial registration: The trial was registered with the International Standard Randomised Controlled Trial Number (ISRCTN) registry (ISRCTN14124474) on 22 October 2020.