Neuropsychological assessment of American Indian/Alaska Native (AI/AN) patients presents challenges due to limited normative data, stigma, possible differential validity of measures, and limited access to healthcare. Additionally, differentiating traumatic brain injury (TBI) and post-traumatic stress disorder (PTSD) is increasingly important for proper diagnosis and treatment of indigenous patients. This case study describes the use of comprehensive neuropsychological testing across two timepoints to assist with treatment planning. The patient was a 38-year-old Native American male referred by primary care to assist in educational, career, and treatment planning. His history was remarkable for TBI status post craniotomy and craniectomy. The patient completed initial and follow-up comprehensive neuropsychological evaluations. Follow-up was completed at 9-months following cranioplasty. On initial evaluation, the patient demonstrated deficits in immediate learning, delayed recall, executive functioning, processing speed, and fine motor abilities consistent with major neurocognitive impairment due to TBI. On follow-up evaluation, the patient demonstrated variable processing speed and executive functioning. Follow-up testing showed improvements in encoding of verbal information and immediate learning of visual information. Modest improvements were noted in processing speed, executive functioning, and fine motor skills. Follow-up testing evidenced declines in immediate learning, spontaneous recall, verbal fluency, and worsening PTSD symptoms. While TBI and PTSD can co-occur, understanding how to differentiate cognitive profiles of each, while considering linguistic, sociocultural, and educational differences, is vital for proper diagnosis and treatment. Adherence to treatments following TBI can promote physical and cognitive improvements, though certain symptoms may worsen due to psychological symptoms, which may present differently across cultures.