Continuous observation of molecular and cellular dynamics in vivo is critical for understanding disease progression and therapeutic response. Conventional approaches, such as imaging or endpoint assays, are limited by their discontinuous nature and the physiological stress they impose on animal models. Here, we present a minimally invasive millimetric implantable device (5 × 5 × 5 mm³) designed for fully autonomous, continuous in vivo fluorescence tracking. The device integrates a miniaturized optical system with low-power on-board electronics, enabling uninterrupted fluorescence recording in close proximity to the biological source. We validated the device by tracking sustained release and systemic clearance of fluorescein isothiocyanate in vivo over 30 h. We further demonstrated long-term utility by continuously tracking tumor-associated fluorescence in a subcutaneous glioma model for 2 weeks. These results present a compact, self-contained device enabling continuous longitudinal fluorescence sensing in animal models, providing a platform for investigating drug delivery, tumor development, and immunological processes in their native microenvironments.