Nanomaterials with unique emission in the second near-infrared window (NIR-II, 1000–1700 nm) are regarded as the promising probes for visualization of tumor vessels and cerebrovascular architecture, because of their superior features such as deep tissue penetration and large imaging resolution. Herein, the new Ce-based fluoride nanoparticles (NPs) with high-efficiency NIR-IIb emission were explored for high-resolution vascular imaging and tumor associated vessel detection. Under the same synthesis conditions, the Ce-based fluoride present the preferential formation CeF3 host and low upconversion (UC) emission, but possess more strong (1.45 times) NIR-IIb downconversion (DC) emission centered at 1525 nm under the irradiation of a 980 nm laser, which is significantly different from the traditional NaYF4:Yb/Er host. Through the efficient cross relaxation between Ce3+ and Er3+, intense NIR-IIb luminescence from Er3+ with high quantum yields were achieved, which make sure the entire mouse body and brain blood vessel imaging with supernal resolution (47.6 μm) were demonstrated. Moreover, the optical imaging in NIR-IIb region guided tumorous vascular visualization was successfully achieved. Therefore, the explored CeF3 NPs with boosting NIR-IIb emission can be employed as new diagnostic bio-probes used in high spatial resolution tumorous vessel detection.