To investigate the relationship between history of anti-inflammatory medication use and delirium risk, as well as long-term mortality. In this retrospective cohort study, subjects recruited between January 2016 and March 2020 were analyzed. Information about anti-inflammatory medication use history including aspirin, NSAIDs, glucosamine, and other anti-inflammatory drugs, was collected. Logistic regression analysis investigated the relationship between anti-inflammatory medications and delirium. Log-rank analysis and cox proportional hazards model investigated the relationship between anti-inflammatory medications and one-year mortality. The data from 1274 subjects were analyzed. The prevalence of delirium was significantly lower in subjects with NSAIDs usage (23.0%) than in those without NSAIDs usage (35.0%) (p < 0.001). Logistic regression analysis controlling for age, sex, dementia status, and hospitalization department showed that the risk of delirium tended to be reduced by a history of NSAIDs use (OR, 0.76 95% CI, 0.55 to 1.03). The one-year mortality in the subjects with NSAIDs (survival rate, 0.879 95% CI, 0.845 to 0.906) was significantly lower than in the subjects without NSAIDs (survival rate, 0.776 95% CI, 0.746 to 0.803) (p < 0.001). A history of NSAIDs use associated with the decreased risk of one-year mortality even after adjustment for age, sex, Charlson Comorbidity Index, delirium status, and hospitalization department (HR, 0.70 95% CI, 0.51 to 0.96). This study suggested that NSAIDs usage was associated with decreased delirium prevalence and lower one-year mortality. The potential benefit of NSAIDs on delirium risk and mortality were shown. •History of NSAIDs use was associated with decreased delirium risk and mortality.•It might be possible that NSAIDs has benefits for patients to prevent delirium and decrease mortality.•Subjects with a history of glucosamine use had lower prevalence of delirium.