Ketamine use has increased recently for the management of acute and chronic pain. Ketamine can cause a variety of neuropsychiatric adverse effects, such as hallucinations, dysphoria, and nightmares. The objective of this study was to explore risk factors for the development of neuropsychiatric adverse effects in ketamine-treated pain. This was a retrospective, single-center cohort study of hospitalized patients who received low dose intravenous (IV) ketamine or oral ketamine for pain. Patients who had a neuropsychiatric adverse effect were compared to those who did not. One hundred and seventy-one patients were included, with 155 receiving IV ketamine and 16 receiving oral ketamine. Overall, 50 (29.2%) had a neuropsychiatric adverse effect and 26 (15.2%) required treatment discontinuation. No significant differences were found between patients who tolerated ketamine and those who did not. Patients who had an adverse effect were numerically less likely to receive benzodiazepines (28% vs 39.7%, = 0.153), as were patients who required discontinuation of ketamine (23.1% vs. 41.4%, = 0.08). In patients receiving ketamine for pain, predicting who may be more likely to experience neuropsychiatric adverse effects remains difficult. Further research is warranted to determine whether benzodiazepines are safe and effective for mitigating these adverse effects in this setting.