The time required for the arrival of an ambulance crew and administration of first aid is critical to clinical outcome, particularly in the case of head injury victims requiring neuroprotective drugs following a car accident, falls, and assaults. Short response times of the medical team, together with proper treatment, can limit injury severity and even save a life before transportation to the nearest medical center. We present a comparative evaluation of five different neuroprotective drugs frequently used in intensive care and operating units in the early phase following traumatic brain injury (TBI): hypertonic saline (HTS), mannitol, morphine, melatonin, and minocycline. The effectiveness of these drugs in terms of changes in brain tissue morphology (cell organelle size, density, distribution, etc.) and biochemical tissue properties (chromophores’ content) was experimentally evaluated through analysis of the spectral reduced scattering and optical absorption coefficient parameters in the near-infrared (NIR) optical range (650 to 1000 nm). Experiments were conducted on anesthetized male mice subjected to a noninvasive closed head weight-drop model of focal TBI (n=50 and n=10 control) and monitored using an NIR diffuse reflectance spectroscopy system utilizing independent source–detector separation and location. After 10 min of baseline measurement, focal TBI was induced and measurements were conducted for 20 min. Subsequently, a neuroprotective drug was administrated and measurements were recorded for another 30 min. This work’s major findings are threefold: first, minocycline was found to improve hemodynamic outcome at the earliest time postinjury. Second, HTS decreased brain water content and inhibited the increase in intracranial pressure. Third, the efficacy of neuroprotective drugs can be monitored noninvasively with diffuse reflectance spectroscopy. The demonstrated ability to noninvasively detect cerebral physiological properties following early administration of neuroprotective drugs underlines the need for more extensive investigation of the combined use of clinical drugs in larger-scale preclinical experiments to find the most beneficial drug treatment for brain injury patients.