Prolonged casualty care (PCC), previously known as prolonged field care, is a system to provide patient care for extended periods of time when evacuation or mission requirements surpass available capabilities. Current guidelines recommend a 7- to 10-day course of ertapenem or moxifloxacin, with vancomycin if methicillin-resistant Staphylococcus aureus is suspected, for all penetrating trauma in PCC. Data from civilian and military trauma have demonstrated benefit for antibiotic prophylaxis in multiple types of penetrating trauma, but the recommended regimens and durations differ from those used in PCC, with the PCC guidelines generally recommending broader coverage. We present a review of the available civilian and military literature on antibiotic prophylaxis in penetrating trauma to discuss whether a strategy of broader coverage is necessary in the PCC setting, with the goal of optimizing patient outcomes and antibiotic stewardship, while remaining cognizant of the challenges of moving medical material to and through combat zones. Empiric extended gram-negative coverage is unlikely to be necessary for thoracic, maxillofacial, extremity, and central nervous system trauma in most medical settings. However, providing the narrowest appropriate antimicrobial coverage is challenging in PCC because of limited resources, most notably, delay to surgical debridement. Antibiotic prophylaxis regimen must be determined on a case-by-case basis based on individual patient factors while still considering antibiotic stewardship. Narrower regimens, which focus on matching up the site of infection to the antibiotic chosen, may be appropriate based on available resources and expertise of treating providers. When resources permit in PCC, the narrower cefazolin-based regimens (with the addition of metronidazole for esophageal or abdominal involvement, or gross contamination of central nervous system trauma) likely provide adequate coverage. Levofloxacin is appropriate for ocular trauma. Ideally, cefazolin and metronidazole should be carried by medics in addition to first-line antibiotics (moxifloxacin and ertapenem, Literature Synthesis and Expert Opinion; Level V).