STUDY DESIGN: Longitudinal, randomized study. OBJECTIVES: (1) Test the safety and feasibility of a ketogenic diet (KD) intervention in the acute stages of spinal cord injury (SCI), (2) assess the effects of a KD on neurological recovery, and (3) identify potential serum biomarkers associated with KD-induced changes in neurological recovery. SETTING: Acute care and rehabilitation facility. METHODS: The KD is a high-fat, low-carbohydrate diet that includes ≈70-80% total energy as fat. Seven participants with acute complete and incomplete SCI (AIS A-D) were randomly assigned to KD (n = 4) or standard diet (SD, n = 3). Neurological examinations, resting energy expenditure analysis, and collection of blood for evaluation of circulating ketone levels were performed within 72 h of injury and before discharge. Untargeted metabolomics analysis was performed on serum samples to identify potential serum biomarkers that may explain differential responses between groups. RESULTS: Our pilot findings primarily demonstrated that KD is safe and feasible to be administered in acute SCI. Furthermore, upper extremity motor scores were higher (p < 0.05) in the KD vs. SD group and an anti-inflammatory lysophospholipid, lysoPC 16:0, was present at higher levels, and an inflammatory blood protein, fibrinogen, was present at lower levels in the KD serum samples vs. SD serum samples. CONCLUSION: Taken together, these preliminary results suggest that a KD may have anti-inflammatory effects that may promote neuroprotection, resulting in improved neurological recovery in SCI. Future studies with larger sample size are warranted for demonstrating efficacy of KD for improving neurological recovery.