Purpose Among head and neck cancers, hypopharyngeal squamous cell carcinoma (HSCC) shows the highest malignancy, which is associated with histologic grading. This study was designed to investigate whether quantitative parameters derived from F-18-fluorodeoxyglucose positron emission tomography/magnetic resonance imaging (F-18-FDG PET/MRI) can preoperatively estimate the histologic grade of HSCC. Methods F-18-FDG PET/MRI of neck was successfully performed in 21 patients with histologically proven HSCC including poorly differentiated group (ten patients) and well-moderately differentiated group (eleven patients). Quantitative parameters derived from FDG-PET, diffusion-weighted imaging (DWI), and dynamic contrast enhanced-magnetic resonance imaging (DCE-MRI) were calculated based on volume of interest drawn on the tumor and compared between two groups. The efficacy of quantitative parameters for the estimation of histologic grades of HSCC was evaluated. Results There were statistically significant differences in mean value of standard uptake value (SUV), apparent diffusion coefficient (ADC), and K-trans derived from F-18-FDG PET/MRI of HSCC between two groups (p < 0.05). There was no statistically significant difference in other quantitative parameters derived from F-18-FDG PET/MRI of HSCC between two groups. The area under the curve (AUC) of the combination of SUVmean, ADC(mean), and K-trans in the estimation of histologic grade of HSCC was 0.936 with sensitivity of 90.0% and specificity of 81.8%. Conclusion The combination of SUVmean, ADC(mean), and K-trans derived from F-18-FDG PET/MRI can accurately predict the histologic grade of HSCC preoperatively.