Overactive inflammatory response and excessive oxidative stress are the main pathophysiological culprits for cerebral ischemia/reperfusion injury (IRI) that arouse neuronal damage . The neurotransmitter acetylcholine (ACh) exerts anti‐inflammatory roles by stimulating α7 nicotinic acetylcholine receptor (α7nAChR) on microglia to activate the cholinergic anti‐inflammatory pathway. Simultaneously, as a circadian rhythm‐dependent hormone , melatonin (MT) possesses promising neuroprotective effects that eliminate reactive oxygen species (ROS) in the ischemic region. Relying on these, a biocompatible fluorescein isothiocyanate (FITC)‐labeled SiO2@PAA‐MT/ACh nanospheres are constructed to effectively alleviate oxidative stress and polarize microglial phenotype to suppress inflammatory response in cerebral IRI. Despite of biosafety and curative effects of ACh and MT, the poor aggregation in ischemic penumbra hinders their neuroprotection. To address that, complement component 5a (C5a) is used as a molecular target for delivery of ACh and MT. C5a conspicuously exists at local inflammatory sites of cerebral IRI, recruits immune cells, and mediates further release of inflammatory cytokines. Upon binding of anti‐C5a (aC5a) aptamers onto FITC‐labeled SiO2@PAA‐MT/ACh nanospheres, they can effectively target the ischemic penumbra and promote neurological recovery. Taken together, the current study suggests that the FITC‐labeled SiO2@PAA‐MT/ACh‐aC5a nanospheres after intravenous (i.v.) administration can act as an effective targeted nanotherapy to salvage neurons in cerebral IRI.