Although penicillin was discovered in 1928, it took over a decade before it was being looked at as a potential solution for a wide variety of infections. At the beginning of World War II, drug companies, supported by the War Production Board, developed processes to scale up production; and by 1943-1944 penicillin was reaching forward military locations.

Soon afterward, later in 1944, the first publication demonstrating the improved outcomes of soldiers treated at the surgical units closest to the front was published. Anecdotal and retrospective reviews throughout subsequent conflicts continued to confirm that delaying treatment until casualties arrived at rear hospitals led to worse outcomes, and recommendations were for field administration, if evacuation times were delayed by several hours.

During the 1993 battle of Mogadishu, a 15-hour delay without antibiotics before treatment at a forward surgical facility resulted in wound infections in 16 of the 58 casualties, for an infection rate of 28%. Subsequently, battlefield antibiotics were recommended in the first TCCC Guidelines.

Later, at the beginning of the war in Iraq, 32 casualties from the drive to Baghdad at the start of the war received early antibiotics on the battlefield and a negligible rate of infections was achieved, despite casualty evacuation often being delayed. And in a separate review of 19 Specials Forces medics and 30 Iraqi military forces treated with antibiotics on the battlefield, no infections were noted despite an 11-hour delay in evacuation.

Animal models have also validated that antibiotics must be given as soon as possible after injury to maximize their ability to prevent wound infections. In one study, for example, a delay of 6 hours had a profound detrimental effect on the infection rate compared to early administration, regardless of the timing of surgery.

A 2007 review of TCCC as used on the battlefields of the Global War on Terrorism noted that there were no reports of adverse effects from the use of battlefield antibiotics, speaking to the safety profile of early administration of antibiotics.

Although antibiotics are not used in most civilian prehospital emergency medical systems with short transport times, definitive care for casualties may be significantly delayed in combat settings due to the longer distances to be covered and tactical constraints on evacuation assets. Antibiotics must be given as soon as possible after injury to maximize their ability to prevent wound infections.