Traumatic brain injury (TBI) is a leading cause of death and disability worldwide; in more severe cases, it may require long-term intensive care treatment and rehabilitation for survivors. Diagnosis has long been based on clinical signs, the Glasgow Coma Scale (GCS), and head computed tomography (CT) scanning. TBI is a highly complex condition affecting several structures; however, the GCS score does not account for the underlying pathophysiological injuries in TBI. In addition, CT findings may be absent in mild TBI (mTBI), the most common form of TBI. This study examined the use of blood biomarkers [β-amyloids 1–40 (Aβ40) and 1–42 (Aβ42), glial fibrillary acidic protein (GFAP), heart fatty acid-binding protein (H FABP), interleukin-10 (IL-10), neurofilament light (NfL), S100 calcium-binding protein B (S100B), and total tau (t-tau)] in TBI research. In the first study, the ability of single biomarkers and their combinations to discriminate between different severities of TBI was examined, along with their capacity to distinguish between mTBI and orthopaedic controls. The ability of the biomarkers to distinguish between different lesion combinations observed on head CT scans was examined in the second study. In the third study, the association between biomarker outliers and clinically significant events and outcomes in ICU-treated patients was evaluated. In the first study, the results indicated that the biomarkers could distinguish mTBI from more severe forms but could not differentiate between mTBI and the orthopaedic controls. In the second study, the biomarkers identified the most severely injured patients, but the sample size was too small to draw conclusions about their ability to differentiate between lesion combinations. In the third study, biomarker outliers appeared to be associated with epileptic seizures/status epilepticus and decompressive hemicraniectomy; however, this finding may be attributable to more severe TBI.