We report the results of a process improvement initiative to examine the current use and safety of prehospital pain medications by U.S. Forces in Afghanistan. Prehospital pain medication data were prospectively collected on 309 casualties evacuated from point of injury (POI) to surgical hospitals from October 2012 to March 2013. Vital signs obtained from POI and flight medics and on arrival to surgical hospitals were compared using one-way analysis of variance test. 119 casualties (39%) received pain medication during POI care and 283 (92%) received pain medication during tactical evacuation (TACEVAC). Morphine and oral transmucosal fentanyl citrate were the most commonly used pain medications during POI care, whereas ketamine and fentanyl predominated during TACEVAC. Ketamine was associated with increase in systolic blood pressure compared to morphine (+7 ± 17 versus −3 ± 14 mm Hg, p = 0.04). There was no difference in vital signs on arrival to the hospital between casualties who received no pain medication, morphine, fentanyl, or ketamine during TACEVAC. In this convenience sample, fentanyl and ketamine were as safe as morphine for prehospital use within the dose ranges administered. Future efforts to improve battlefield pain control should focus on improved delivery of pain control at POI and the role of combination therapies.