Human papillomavirus associated head and neck cancer (HPV + HNC) is rising globally, emphasizing the need for improved therapeutic and screening strategies. To test novel therapies and study HPV-related disease progression, it is vital to develop relevant preclinical models. However, many fail to address critical concerns, including generating a representative immune microenvironment and adequately modeling HPV-driven malignant transformation. Recent multi-omics studies reveal the significance of HPV integration location in HPV-related carcinogenesis and highlight the necessity of targeted treatment methods. Thus, we have developed a murine model of HPV16 + HNC modifying the published CRISPR-based Somatic Oncogene kNock-In for Cancer Modeling (CRISPR-SONIC) system for precise integration of HPV oncogenes. We showed that CRISPR-SONIC knock-in of Kras, HPV16 E6 and E7, and a luciferase reporter at the murine β-actin 3'-UTR locus could induce spontaneous buccal tumors with sarcomatous morphology under transient or selective immunosuppression. Both preventative and therapeutic pNGVL4a-CRT/E7(detox) DNA vaccination could induce HPV16 E7-specific immune response and reduce tumor growth. Furthermore, CRISPR-SONIC knock-in of HPV16 E6 and E7 with co-delivery of HNC-relevant oncogenes AKT and c-Myc produced tumors in NSG mice capturing the characteristic carcinomic morphology of HPV + HNC. Overall, our model offers a robust platform for evaluating new therapies and exploring HPV-related carcinogenesis.