Background: Oropharyngeal squamous cell carcinoma (OPSCC) associated with human papillomavirus (HPV) has higher rates of locoregional control and a better prognosis than HPV-negative OPSCC. These differences are due to some unique biological characteristics that are also visible through advanced imaging modalities. We investigated the ability of a multifactorial model based on both clinical factors and diffusion-weighted imaging (DWI) to determine the HPV status in OPSCC. Methods: The apparent diffusion coefficient (ADC) and the perfusion-free tissue diffusion coefficient D were derived from DWI, both in the primary tumor (PT) and lymph node (LN). First- and second-order radiomic features were extracted from ADC and D maps. Different families of machine learning (ML) algorithms were trained on our dataset using five-fold cross-validation. Results: A cohort of 144 patients was evaluated retrospectively, which was divided into a training set (n = 95) and a validation set (n = 49). The 50th percentile of DPT, the inverse difference moment of ADCLN, smoke habits, and tumor subsite (tonsil versus base of the tongue) were the most relevant predictors. Conclusions: DWI-based radiomics, together with patient-related parameters, allowed us to obtain good diagnostic accuracies in differentiating HPV-positive from HPV-negative patients. A substantial decrease in predictive power was observed in the validation cohort, underscoring the need for further analyses on a larger sample size.