Photobiomodulation (PBM) is a therapeutic modality that has gained increasing interest in neuroscience applications, including acute traumatic brain injury (TBI). Its proposed mechanisms for therapeutic effect when delivered to the injured brain include antiapoptotic and anti-inflammatory effects. This systematic review summarizes the available evidence for the value of PBM in improving outcomes in acute TBI and presents a meta-analysis of the pre-clinical evidence for neurological severity score (NSS) and lesion size in animal models of TBI. A systematic review of the literature was performed, with searches and data extraction performed independently in duplicate by two authors. Eighteen published articles were identified for inclusion: seventeen pre-clinical studies of in vivo animal models and one clinical study in human patients. The available human study supports safety and feasibility of PBM in acute moderate TBI. For pre-clinical studies, meta-analysis for NSS and lesion size were found to favor intervention versus control. Subgroup analysis based on PBM parameter variables for these outcomes was performed. Favorable parameters were identified as: wavelengths in the region of 665 nm and 810 nm; time to first administration of PBM ≤4 h; total number of daily treatments ≤3. No differences were identified between pulsed and continuous wave modes or energy delivery. Mechanistic substudies within included in vivo studies are presented and were found to support hypotheses of antiapoptotic, anti-inflammatory, and pro-proliferative effects, and a modulation of cellular metabolism. This systematic review provides substantial meta-analysis evidence of the benefits of PBM on functional and histological outcomes of TBI in in vivo mammalian models. Study design and PBM parameters should be closely considered for future human clinical studies.