Objective: To investigate the effect of donepezil on cognitive ability in patients who have sustained a traumatic brain injury (TBI). We hypothesized that donepezil, an acetylcholinesterase inhibitor, would enhance cognitive recovery beyond that of usual care in an acute rehabilitation facility. Methods: This retrospective, longitudinal analysis included 55 patients who were non-randomly prescribed donepezil during acute care and compared them to 74 patients who received usual rehabilitation treatment. All 129 patients completed neuropsychological assessment at two time points. Donepezil was increased from 5 to 10 mg 7–10 days after initiation and maintained until follow-up cognitive assessment. Main outcomes: Primary cognitive abilities of interest included processing speed, attention and memory. Cognitive and functional abilities were assessed by a standard neuropsychological battery for TBI. Results: Propensity scores were used to adjust for differences between groups. Mixed effect model analysis showed no significant differences between treatment and control groups on all neuropsychological subtests over time. Conclusions: Acute administration of donepezil did not significantly improve measures of cognitive or functional ability beyond that of treatment as usual in patients with moderate-to-severe TBI.