Background Acute ischemic stroke, a clinical disorder caused by nontraumatic cerebrovascular disease, has an acute onset,frequently causesneurological deficit, and may persist for >24 hours or can be fatal in <24 hours. This studyaimed to assess the red cell width distribution (RDW) and the mean platelet volume (MPV) in predicting 30-day mortality in acute ischemic stroke patients. In general, patients with acute ischemic stroke have a rather high mortality rate in the first 30 days due to various complications, but post the 30-day mark, the prognosis is comparatively better. Material and methods The present study was conducted on patients with a confirmed diagnosis of acute ischemic stroke based on history, physical examination, CT scan, and/or diffusion-weighted MRI scan performed during the first 24 hours. It was a prospective and cross-sectional study done at Saveetha Medical College over a period of two years. The data was collected by using the intra-hospital network and was analyzed using the IBM SPSS Statistics for Windows, Version 20 (Released 2011; IBM Corp., Armonk, New York, United States). Results In the present study, among 100 patients, the mean agewas57.4 ± 13.36 years. About 55% of our subjects were males in our study. The RDW on the 1stday was 14.17 ± 0.708, and it reduced drastically on the 30thday to1st 13.55 ± 1.11, and it was statically significant (p = 0.000). The MPVon day 1 was 11.11 ± 0.969 and, on day 30, was 10.82 ± 0.90; the MPV was reduced considerably on day 30, which was statistically significant (p = 0.000). RDW on the 1stday was significantly correlated with the MPV and the volume ofstroke. Thecorrelation wassignificant at the 0.01 level (two-tailed). On the 30thday of acute ischemic stroke patients, the red blood cell (RBC)width was significantly correlated with the MPV. The correlation was significant at the 0.01 level (two-tailed). At the end of 30 days, 10% mortality was observed in the present study. Day 30 saw a significant decrease in the MPV and RDW, particularly in the moderate to severe and severe categories. The National Institutes of Health Stroke Scale (NIHSS) score and the volume of stroke were significantly associated with the 30-dayoutcome. Conclusion The RDW and the MPV are well correlated in predicting the 30-day mortality in acute ischemic stroke patients. This could potentially be used as a significant marker for predicting mortality in stroke patients in the future, but to increase the generalization, further studies need to be carried out at other demographically distinct medical centers.