A major fire at sea is among the most devastating events that can occur while a U.S. Navy combatant vessel is underway. Since World War II, no attack on a large U.S. Navy capital ship has occurred during combat operations. However, increasing global tensions raise the threat of future peer adversary naval combat, and shipboard medical caregivers must be prepared for mass casualty events in the deployed maritime environment. To better prepare modern naval caregivers for this possibility, we reviewed mass casualty events from major fires aboard large U.S. Navy aircraft carriers from 1950 through 2020 to summarize available objective data and identify lessons learned. Underway fires from any cause aboard U.S. Navy aircraft carriers and large amphibious assault ships causing more than 10 casualties (injuries + deaths) were reviewed from 1950 through 2020 using available open access sources including literature review, the Naval Safety Command mishap database, and U.S. Navy Judge Advocate Manual reports. Of 246 fires identified, 27 met inclusion criteria resulting in 1,634 casualties with a combined crew mortality of 23% of those injured. In the 16 events with at least 1 death, 2.0% of the total crew was injured with a combined mortality of 28%. All mishaps occurred while underway during routine training or combat operations; none were caused by an enemy combatant attack. Those events affecting more than 5% of the crew were particularly devastating resulting in a mortality rate of 29% of 1,056 total casualties. Given that main medical spaces may be damaged or destroyed during major fires from any cause, identified lessons learned included the need for (1) distributed medical supplies, (2) flexible medical treatment locations throughout the ship, (3) specific training to prepare non-physician caregivers and non-medical first responders to provide burn and hemorrhagic shock resuscitation, airway management, and prolonged care at or near the point of injury, and (4) the prolonged holding capability of critically ill burned and injured patients if evacuation off the ships is unavailable. Shipboard fires underway pose a significant threat to crew safety with a mortality of nearly a quarter of those injured. These fire mass casualty events immediately overwhelm shipboard medical capabilities requiring a complex response from all hands beginning with non-medical first responders. Notably, all events occurred outside of direct enemy combat, potentially underestimating the impact and number of casualties of a shipboard fire during naval combat. Advances in peer weaponry and the threat of future conflict emphasize the need for pre-deployment burn care training for all shipboard medical caregivers as well as advanced airway and resuscitation training for non-physician caregivers. This review underscores the profound impact of shipboard fires on crew safety, highlighting the critical need for enhanced preparedness and response strategies to prepare for fire-related mishaps during routine operations and naval combat.