It is crucial to inhibit the neuroinflammation response as it is a prominent factor contributing to the pathogenesis of neurodegenerative disorders. However, the limited development of neuroinflammation models dramatically hinders the efficiency of nanomedicine discovery. In recent years, the optically transparent zebrafish model provided unique advantages for in vivo imaging of the whole body, allowing the progression of the disease to be visualized. In this study, a lipopolysaccharide (LPS)-mediated zebrafish neuroinflammation model was established to visualize the brain distribution and quickly evaluate the anti-inflammation effect of human ferritin-loaded curcumin (Cur@HFn) nanoparticles. The Cur@HFn drug delivery system was successfully prepared and characterized. The HFn nanocage demonstrated significant brain accumulation and prolonged circulation in a zebrafish larval model. In the LPS-induced zebrafish model, Cur@HFn significantly reduced neutrophil recruitment within the brain region of the LPS-treated zebrafish. Additionally, Cur@HFn mitigated nitric oxide (NO) release and downregulated the mRNA expression levels of proinflammatory cytokines, including TNF-α and IL-1β. Lastly, Cur@HFn significantly reduced the damage of raphe nucleus neurons and alleviated the locomotion deficiency caused by LPS. Overall, our findings highlight that Cur@HFn is a promising drug delivery system for the targeted treatment of brain disorders. This zebrafish neuroinflammation model could be used for high-throughput in vivo drug screening and discovery.