We aimed to predict CD44 expression and assess its prognostic significance in patients with high-grade gliomas (HGG) using non-invasive radiomics models based on machine learning. Enhanced magnetic resonance imaging, along with the corresponding gene expression and clinicopathological data, was downloaded from online database. Kaplan-Meier survival curves, univariate and multivariate COX analyses, and time-dependent receiver operating characteristic were used to assess the prognostic value of CD44. Following the screening of radiomic features using repeat least absolute shrinkage and selection operator, two radiomics models were constructed utilizing logistic regression and support vector machine for validation purposes. The results indicated that CD44 protein levels were higher in HGG compared to normal brain tissues, and CD44 expression emerged as an independent biomarker of diminished overall survival (OS) in patients with HGG. Moreover, two predictive models based on seven radiomic features were built to predict CD44 expression levels in HGG, achieving areas under the curves (AUC) of 0.809 and 0.806, respectively. Calibration and decision curve analysis validated the fitness of the models. Notably, patients with high radiomic scores presented worse OS (p < 0.001). In summary, our results indicated that the radiomics models effectively differentiate CD44 expression level and OS in patients with HGG.