Study design: Analysis of data from two cohorts of Spinal Cord Injury Model Systems Database (SCIMS) participants, pre-pandemic (2017–2019, n = 6368) and during pandemic (2020, n = 1889). Objectives: To examine differences in substance use during the pandemic compared to the years prior to the pandemic. Setting: 19 SCIMS Centers. Methods: Participant characteristics, wellness (depression, life satisfaction, resilience), participation, and substance use between the two cohorts were compared. Multiple logistic regression examined the association of the pandemic with substance use after accounting for other factors. Results: Characteristics of the two cohorts were similar. Cannabis and sedative uses were not greatly different (28.8% vs 25.1%, and 8.3% vs 6.6%) but did reach statistical significance. Non-prescribed opioid use was double for the pandemic group (6.6% vs 3.3%). Alcohol use patterns were similar across the two cohorts. Measures of wellness were similar, while the pandemic group reported lower participation. The odds of use of cannabis, sedatives, and opioids were 1.3, 1.3, and 2.2 times greater, respectively, for the pandemic cohort after accounting for demographics, wellness, and participation. Greater use of non-prescribed opioids was reported during the pandemic in the South compared to prior to the pandemic (13.8% vs 6.1%). Conclusions: The pandemic may have been associated with increased use of non-prescribed substances in the traumatic spinal cord injury population. Efforts to pursue longitudinal investigations would be warranted for definitive analysis of trends. The provision of demonstrably effective substance use treatment resources delivered via accessible methods will likely be needed in this population, particularly opioid treatment.