<p>Early exposure to toxic substances is a known risk factor for neurotoxicity. The present study is aimed at exploring the neurotoxicity of nano-alumina (AlNPs) and aluminum chloride (AlCl₃) in zebrafish at 144&#xa0;h post-fertilization (hpf) and at investigating the role of the type II triggering receptor expressed on myeloid cells (trem2) among them. Zebrafish embryos within the four-cell stage were exposed to control, negative control, trem2 knockdown, AlCl₃, AlCl₃ + trem2 knockdown, AlNPs, and AlNPs + trem2 knockdown until 144 hpf. 500 pL of lentivirus containing trem2 inhibitor at 5 × 10⁸ TU/mL was microinjected into the yolk sacs to achieve trem2 knockdown. AlCl₃ and AlNPs were applied at 50&#xa0;mg/L. Neurobehavior, AChE and SOD levels, and the expression of trem2 and neurodevelopmental genes were measured. AlNPs significantly increased the average speed while decreasing the absolute angle compared to AlCl₃. Upon trem2 knockdown, time spent in the outer zone, distance travelled, and accelerated speed were further reduced in both AlCl₃ and AlNPs groups. The trem2 loss also exacerbated the suppression of AChE and SOD levels, trem2, α1-tubulin, and mbp gene levels in the AlCl₃ and AlNPs groups. In conclusion, AlCl₃ induced higher neurotoxicity than AlNPs, and these effects were intensified by trem2 knockdown. Studying larvae allows us to capture neurodevelopmental disturbances during critical stages of brain formation, offering a more comprehensive assessment of the risks and therapeutic potential of targeting trem2 in Al- and AlNPs-induced neurotoxicity.</p> Graphical Abstract <p></p>