Recently, various second near-infrared window (NIR-II, 1000-1700 nm) fluorophores have been synthesized for in vivo imaging with nonradiation, high resolution, and low autofluorescence. However, most of the NIR-II fluorophores, especially inorganic nanoprobes, are mainly retained in the reticuloendothelial system (RES) such as the liver and spleen, leading to long-term safety concerns. Herein, a type of lanthanide-based excretable NIR-II nanoparticle, RENPs@Lips, which can be quickly cleared out of body after intravenous administration with half-lives of 23.0 h for the liver and 14.9 h for the spleen, is reported. Interestingly, over 90% of RENPs@Lips can be excreted through a hepatobiliary system within 72 h postinjection. The moderate blood half-time ( = 17.96 min) allows for multifunctional applications in delineating the hemodynamics of vascular disorders (artery thrombosis, ischemia, and tumor angiogenesis) and monitoring blood perfusion in response to acute ischemia. In addition, RENPs@Lips exhibit high performance in identifying orthotopic tumor vessels intraoperatively and embolization surgery under NIR-II imaging navigation. Moreover, excellent signal-to-background ratio (SBR) is successfully achieved to facilitate sentinel lymph nodes biopsy (SLNB) with tumor-bearing mice. The high biocompatibility, favorable excretability, and outstanding optical properties warrant RENPs@Lips as novel promising NIR-II nanoparticles for future applications and translation into an interdisciplinary amalgamation of research in diverse fields.