Study Design: Systematic review. Objective: Providing a comprehensive review of spinal cord injury cost of illness studies to assist health-service planning. Methods: We conducted a systematic review of the literature published from Jan. 1990 to Nov. 2020 via Pubmed, EMBASE, and NHS Economic Evaluation Database. Our primary outcomes were overall direct health care costs of SCI during acute care, inpatient rehabilitation, within the first year post-injury, and in the ensuing years. Results: Through a 2-phase screening process by independent reviewers, 30 articles out of 6177 identified citations were included. Cost of care varied widely with the mean cost of acute care ranging from $290 to $612,590; inpatient rehabilitation from $19,360 to $443,040; the first year after injury from $32,240 to $1,156,400; and the ensuing years from $4,490 to $251,450. Variations in reported costs were primarily due to neurological level of injury, study location, methodological heterogeneities, cost definitions, study populations, and timeframes. A cervical level of the injury, ASIA grade A and B, concomitant injuries, and in-hospital complications were associated with the greatest incremental effect in cost burden. Conclusion: The economic burden of SCI is generally high and cost figures are broadly higher for developed countries. As studies were only available in few countries, the generalizability of the cost estimates to a regional or global level is only limited to countries with similar economic status and health systems. Further investigations with standardized methodologies are required to fill the knowledge gaps in the healthcare economics of SCI.