We investigated the relationship among red cell distribution width (RDW), to total serum calcium (TSC) ratio (RCR), and in-hospital mortality in patients with acute ischemic stroke (AIS). This study was a retrospective analysis. The data of 2700 AIS patients was retrospectively analyzed from the Medical Information Mart for Intensive Care database (version IV). The main outcome of interest was in-hospital mortality. A Cox proportional hazards regression model was used to determine whether RCR was independently associated with in-hospital mortality. The Kaplan–Meier method was used to plot the survival curves for RCR. Subgroup analyses were performed to measure the mortality across various subgroups. The area under curve (AUC) of receiver operating characteristic curve (ROC) was calculated to ascertain the quality of RCR as a predictor of in-hospital mortality in patients with AIS. In the multivariate analysis, statistically significant differences were identified in age, ethnicity, length of ICU stay, mechanical ventilation, sequential organ failure assessment (SOFA) score, RDW, hemoglobin, RCR, whether taking anticoagulants, hyperlipidemia, and atrial fibrillation (P < .05). A threshold inflection point value of 1.83 was obtained through a two-piecewise regression model. There was a non-linear relationship between RCR and hospital mortality in patients with AIS. The hazard ratio (HR) and the 95% confidence intervals (CI) on the right and left of the inflection point were 0.93 (0.57-1.51; P = .7660) and 2.96 (1.37–6.42; P = .0060), respectively. The Kaplan–Meier curve indicated that survival rates were higher when RCR was ≤ 1.83 and lower when RDW was > 1.83 after adjustment for age, gender, BMI, ethnicity. The area under curve (AUC) of RCR was 0.715. A higher RCR was associated with an increased risk of in-hospital mortality in patients with AIS.