Oral cancer is a common malignant tumor of the head and neck, and surgery combined with radiotherapy and chemotherapy is the primary treatment modality. However, a positive resection margin that may lead to recurrence after surgery has always been a critical issue to address. Furthermore, radiotherapy and chemotherapy also have shortcomings such as resistance to chemotherapy and radiation, lack of targeting, and severe side effects. Therefore, exploring new methods of tumor surgical navigation and tumor treatment is of great significance for oral cancer. Although, the emerging near-infrared II (NIR-II, 1,000–1,700 nm) region fluorescent imaging has revolutionized surgical navigation, a high tumor-targeting fluorescent probe remains lacking. Furthermore, while emerging photothermal therapy (PTT) can overcome chemoradiotherapy’s shortcomings and achieve precise treatment of tumors, its clinical application is still limited by the lack of high photothermal conversion efficiency, high photothermal stability, and highly penetrating materials. Herein, a NIR-II dye SQ890 is developed for tumor imaging and PTT of oral cancer. By assembling into nanoparticles (NPs) and being modified with epithelial growth factor receptor (EGFR)-targeting peptides GE11, SQ890 NPs-Pep can specifically accumulate in tumor sites via active targeting, and realize photoacoustic/NIR-II fluorescence dual-modality imaging-guided PTT of oral cancer.