Background Cognitive impairments commonly occur after traumatic brain injury (TBI) and affect daily functioning. Cortisol levels, which are elevated during acute hospitalization for most individuals after severe TBI, can influence cognition, but this association has not been studied previously in TBI. Objective We hypothesized that serum and cerebral spinal fluid (CSF) cortisol trajectories over days 0–5 post-injury are associated with cognition 6-month post-injury. Methods We examined 94 participants with severe TBI, collected acute serum and/or CSF samples over days 0–5 post-injury, and compared cortisol levels to those in 17 healthy controls. N = 88 participants had serum, and n = 84 had CSF samples available for cortisol measurement and had neuropsychological testing 6 months post-injury. Group based trajectory analysis (TRAJ) was used to generate temporal serum and CSF cortisol profiles which were examined for associations with neuropsychological performance. We used linear regression to examine relationships between cortisol TRAJ groups and both overall and domain-specific cognition. Results TRAJ analysis identified a high group and a decliner group for serum and a high group and low group for CSF cortisol. Multivariable analysis showed serum cortisol TRAJ group was associated with overall cognitive composites scores ( P = .024) and with executive function ( P = .039) and verbal fluency ( P = .029) domain scores. CSF cortisol TRAJ group was associated with overall cognitive composite scores ( P = .021) and domain scores for executive function ( P = .041), verbal fluency ( P = .031), and attention ( P = .034). Conclusions High acute cortisol trajectories are associated with poorer cognition 6 months post-TBI.