Reduced field-of-view diffusion-weighted imaging (reduced-FOV DWI) is a promising technique for assessing tumor heterogeneity and microstructure. In this study, we evaluated the ability of reduced-FOV DWI to identify specific patterns associated with human papillomavirus (HPV) exposure in head and neck squamous cell carcinoma (HNSCC). Whole-lesion analysis of the tumor was performed on reduced-FOV and conventional DWI using a multi b value sequence. The extracted parameters included the 10th-90th percentile of the apparent diffusion coefficient (ADC) and fractional blood volume (fBV), skewness, and kurtosis. The differences between HPV-negative and HPV-positive tumors were greater for reduced-FOV DWI. ADC was significantly lower in HPV-positive tumors (reduced-FOV DWI: p < 0.001, r = 0.50; conventional DWI: p < 0.001, r = 0.49). The fBV was significantly lower in HPV-positive tumors on reduced-FOV DWI (reduced-FOV DWI: p < 0.001, r = 0.47; conventional DWI: not statistically significant). Moreover, there were significant differences between parameters derived from reduced-FOV and conventional DWI (ADC: p < 0.001, fBV: p < 0.001; skewness: p < 0.001, kurtosis: p = 0.008; kurtosis: p < 0.001). In conclusion, DWI parameters varied depending on HPV status and the differences between HPV-positive and HPV-negative tumors were greater for reduced-FOV DWI. The reduced-FOV DWI better reflected histopathology than did conventional DWI.