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Abstract Objective Meningiomas are a molecularly ill-defined heterogeneous group of indolent intracranial tumors. Though, WHO grade 1 tumors are histologically benign, sometimes they transform into malignant and may be recurrent which remains always challenging to clinicians. Therefore, the current study sought to discover the clinical relevance of CD44 in meningioma patients. Method Protein expression of CD44 was investigated using immunohistochemistry in a total of 70 meningioma patients. Immunoscore performed using modified H-score, CD44 expression correlated with clinicopathological parameters and progression-free survival (PFS) and overall survival (OS). Univariate and multivariate survival analysis was analyzed. The data was evaluated using SPSS statistical software and P-value ≤ 0.05 was considered as significant. Results The membranous and cytoplasmic protein expression of CD44 was noted in meningioma tumors. Based on H-score, the weak (0–190 score) and strong (191–300 score) immunoreactivity was observed in 62.9% and 37.1% of patients, respectively. A statistically significant positive correlation was found between strong CD44 expression and WHO grade 2/3 tumors (χ 2 = 33.551, r = + 0.692, P = 0.0001), and with the presence of brain invasion (χ 2 = 19.521, r = + 0.528, P = 0.001). In Kaplan–Meier univariate survival analysis for PFS and OS, apart from WHO grade of tumors (PFS; log-rank = 12.309, P = 0.0001, OS; log-rank = 17.830, P = 0.0001) and brain invasion status (PFS; log-rank = 11.941, P = 0.001, OS; log-rank = 13.554, P = 0.0001) CD44 expression (PFS; log-rank = 14.942, P = 0.0001, OS; log-rank = 20.986, P = 0.0001) remained significant prognostic factor for PFS and OS. In multivariate survival analysis, at step 1, only CD44 remained independent prognosticator for PFS (HR = 11.014, 95% CI = 2.256–23.602, P = 0.001) and OS (HR = 8.553, 95% CI = 2.831–25.847, P = 0.0001). In relation to treatment offered, patients with strong CD44 expression and if treated with surgery followed by adjuvant radiotherapy showed a high incidence of death (log-rank = 13.402, P = 0.0001) as compared to patients treated with surgery only. Receiver operating characteristic (ROC) curves also confirmed a good efficacy of CD44 as a prognosticator for disease outcome (PFS; P = 0.0001, OS; P = 0001). Conclusion Our overall findings addressed that a study of CD44 protein expression would be beneficiated to meningioma patients from unnecessary overtreatment and drug-induced toxicity. Also, CD44 could be one of the promising biomarkers that might differentiate high-risk meningioma patients for better treatment management.