A biomimetic microglial nanoparticle system (termed MNPs@PLX and represented by fireball) was established for precise microglial delivery of FDA‐approved colony stimulation factor 1 receptor (CSF1R) antagonist PLX3397 to attenuate cognitive decline, dysfunctional synaptic plasticity, and pro‐inflammatory response caused by microglia activation (represented by dragon) in the hippocampus of Cntnap4deficiency mice. This work uncovers a new avenue for biomimetic nanoparticle strategy in neurodegenerative diseases intervention.