The study's objective was to assess the connection between ramelteon usage and mortality from any cause in ischemic stroke patients in the intensive care unit (ICU). Utilizing the MIMIC-IV database, we analyzed a cohort of adult patients who had been diagnosed with ischemic stroke. During their time in the hospital, patients were sorted into ramelteon and non-ramelteon groups according to drug exposure. To achieve balance in baseline covariates, propensity score matching (PSM) was utilized. The primary focus was on mortality from all causes over 28 days, with secondary focuses on all-cause mortality over 90 and 365 days. Using Cox proportional hazards models, hazard ratios (HR) and 95% confidence intervals (CI) were estimated, taking into account potential confounding factors. Subgroup analyses were done to assess effect modification across clinical strata. The study encompassed 3413 patients, with 535 pairs matched after PSM. Ramelteon use was significantly associated with decreased 28-day all-cause mortality rates both before and after PSM, with adjusted HR of 0.34 and 0.23, both with P < 0.001. The fully adjusted post-PSM models showed similar protective associations for 90-day (HR = 0.43) and 365-day (HR = 0.55) all-cause mortality, both with P < 0.001. Prolonged use of ramelteon for more than 14 days and cumulative doses exceeding 300 mg were consistently linked to lower all-cause mortality at all time intervals. Through subgroup and sensitivity analyses, the associations were confirmed to be consistent across different clinical strata. In critically ill patients with ischemic stroke, ramelteon usage was independently associated with lower short- and long-term all-cause mortality.© 2025. The Author(s).