This research work presents an innovative charge-modulated hybrid dielectric organic thin-film transistor (CM-HD OTFT) biosensor designed for the early detection of the breast cancer biomarker C-erbB-2 in saliva and serum samples. By incorporating a dual-dielectric structure and a sensing cavity adjacent to dielectric layers, the biosensor significantly enhances interface quality and biomarker immobilization. To facilitate specific binding, the cavity surface is functionalized with 3-aminopropyltriethoxysilane (APTES), promoting conjugation with C-erbB-2 biomolecules. The detection mechanism relies on the modulation of interface charge density due to varying concentrations of the C-erbB-2 biomarker in normal versus malignant saliva/serum samples. These charge variations directly influence the device’s electrical characteristics, thereby enabling sensitive early-stage breast cancer detection. A numerical charge-equivalent model for C-erbB-2 has been developed, and the detection process has been thoroughly analyzed using 2D numerical simulations in ATLAS SILVACO. The sensitivity of the biosensor is evaluated in terms of drain current and the switching ratio, achieving values of 2.5 × 104 (6.54 × 104) and 9.8 × 109 (7.5 × 108) for saliva (serum) samples, respectively. Moreover, additional sensing metrics such as linearity, limit of detection (LoD), and noise characteristics are investigated, demonstrating superior sensitivity compared to existing biosensors. To further optimize performance, the study also refines the cavity thickness from 8 nm to 12 nm, ensuring improved detection efficiency. These advancements suggest that the CM-HD OTFT biosensor holds strong potential for point-of-care applications in early-stage breast cancer detection.