Background: Ischemic stroke remains one of the leading causes of morbidity and mortality worldwide. Thus, developing more efficient tools to diagnose the condition promptly is critical. Mean platelet volume (MPV) and C-reactive protein (CRP), markers that reflect thrombotic and inflammatory pathways, respectively, are closely associated with the pathophysiology of ischemic stroke and may serve as biomarkers. Aims and Objectives: This study aimed to assess the diagnostic potential of MPV and CRP when measured in patients with ischemic stroke against these markers’ levels in healthy persons. The association between these two biomarkers, as measured in ischemic stroke cases, was also explored. Materials and Methods: A cross-sectional comparison study recruited 54 patients with acute ischemic stroke and 54 age- and sex-matched healthy persons at Government Medical College, Kozhikode. MPV and CRP were measured 24 h post-stroke. The variable comparisons across the groups were made using SPSS; similarly, correlation tests were run considering all subjects experiencing stroke. Results: Patients with ischemic stroke had higher MPV levels of 9.17 ± 0.48 fL than controls: 8.25 ± 0.45 fL P < 0.001. The CRP levels were similarly higher in the stroke group: 3.087 ± 1.11 mg/L versus 0.437 ± 0.24 mg/L, P < 0.001. MPV and CRP had a significant positive correlation after analyzing patients with ischemic stroke (r = 0.332, P = 0.014). Conclusion: The results show that MPV and CRP are robust biomarkers for diagnosing ischemic stroke early, as they represent the underlying inflammatory and thrombotic processes. Implementing them in routine checks can promote early detection and management, improving patient outcomes. Further, longitudinal research is critical to confirm and refine their predictive value.