Background Antibiotic prophylaxis is routinely administered for most operative procedures, but their utility for certain bedside procedures remains controversial. We performed a systematic review and meta-analysis and developed evidence-based recommendations on whether trauma patients receiving tube thoracostomy (TT) for traumatic hemothorax or pneumothorax should receive antibiotic prophylaxis. Methods Published literature was searched through MEDLINE (via PubMed), Embase (via Elsevier), Cochrane Central Register of Controlled Trials (via Wiley), Web of Science and ClinicalTrials.gov databases by a professional librarian. The date ranges for our literature search were January 1900 to March 2020. A systematic review and meta-analysis of currently available evidence were performed using the Grading of Recommendations Assessment, Development and Evaluation methodology. Results Fourteen relevant studies were identified and analyzed. All but one were prospective, with eight being prospective randomized control studies. Antibiotic prophylaxis protocols ranged from a single dose at insertion to 48 hours post-TT removal. The pooled data showed that patients who received antibiotic prophylaxis were significantly less likely to develop empyema (OR 0.47, 95% CI 0.25 to 0.86, p=0.01). The benefit was greater in patients with penetrating injuries (penetrating OR 0.25, 95% CI 0.10 to 0.59, p=0.002, vs blunt OR 0.25, 95% CI 0.06 to 1.12, p=0.07). Administration of antibiotic prophylaxis did not significantly affect pneumonia incidence or mortality. Discussion In adult trauma patients who require TT insertion, we conditionally recommend antibiotic prophylaxis be given at the time of insertion to reduce incidence of empyema. PROSPERO registration number CRD42018088759.