Near-infrared-II (NIR-II) bioimaging gradually becomes a vital visualization modality in the real-time investigation for fundamental biological research and clinical applications. The favorable NIR-II contrast agents are vital in NIR-II imaging technology for clinical translation, which demands good optical properties and biocompatibility. Nevertheless, most NIR-II contrast agents cannot be applied to clinical translation due to the acute or chronic toxicity caused by organ retention in vivo imaging. Therefore, it is critical to understand the pharmacokinetic properties and optimize the clearance pathways of NIR-II contrast agents in vivo to minimize toxicity by decreasing organ retention. In this review, the clearance mechanisms of biomaterials, including renal clearance, hepatobiliary clearance, and mononuclear phagocytic system (MPS) clearance, are synthetically discussed. The clearance pathways of NIR-II contrast agents (classified as inorganic, organic, and other complex materials) are highlighted. Successively analyzing each contrast agent barrier, this review guides further development of the clearable and biocompatible NIR-II contrast agents.