Background Traumatic brain injury (TBI) has a complex pathophysiology that has historically been poorly understood. New evidence on the pathophysiology, molecular biology, and diagnostic studies involved in TBI have shed new light on optimizing rehabilitation and recovery. The goal of this study was to assess the effect of osteopathic manipulative treatment (OMT) on peripheral and central glial lymphatics in patients with severe TBI, brain edema, and elevated intracranial pressure (ICP) by measuring changes in several parameters regularly used in management. Methodology This was a retrospective study at a level II trauma center that occurred in 2018. The study enrolled patients with TBI, increased ICP, or brain edema who had an external ventricular drain placed. Patients previously underwent a 51-minute treatment with OMT with an established protocol. Patients received 51 minutes of OMT to the head, neck, and peripheral lymphatics. The ICP, cerebrospinal fluid (CSF) drainage, optic nerve sheath diameter (ONSD) measured by ultrasonography, and Neurological Pupil Index (NPi) measured by pupillometer were recorded before, during, and after receiving OMT. Results A total of 11 patients were included in the study, and 21 points of data were collected from the patients meeting inclusion criteria who received OMT. There was a mean decrease in the ONSD of 0.62 mm from 6.24 mm to 5.62 mm (P = 0.0001). The mean increase in NPi was 0.18 (P = 0.01). The mean decrease in ICP was 3.33 mmHg (P= 0.0001). There was a significant decrease in CSF output after treatment (P = 0.0001). Each measurement of ICP, ONSD, and NPi demonstrated a decrease in overall CSF volume and pressure after OMT compared to CSF output and ICP prior to OMT. Conclusions This study demonstrates that OMT may help optimize glial lymphatic clearance of CSF and improve brain edema, interstitial waste product removal, NPi, ICP, CSF volume, and ONSD. A holistic approach including OMT may be considered to enhance management in TBI patients. As TBI is a spectrum of disease, utilizing similar techniques may be considered for all forms of TBI including concussions and other diseases with brain edema. The results of this study can better inform future trials to specifically study the effectiveness of OMT in post-concussive treatment and in those with mild-to-moderate TBI.