Cyanobacterial blooms constitute a global ecological problem that can seriously threaten human health. One of the most common bloom-forming cyanobacteria in freshwater is Microcystis aeruginosa, whose secretion of toxic substances (microcystins, MCs) have strong liver toxicity and endanger the health of exposed people through contaminated aquatic products and drinking water. However, few studies on the neurotoxicity of M. aeruginosa to zebrafish have simulated the process of an actual cyanobacterial bloom. In this study, we used the zebrafish (Danio rerio) as an effective model organism to study the acute neurotoxicity of M. aeruginosa, and to clarify its principal mechanism of action. A total of 82 upregulated and 26 downregulated proteins were detected by quantitative proteomics analysis in zebrafish brain after exposure to M. aeruginosa. Intriguingly, these proteins with changed expression were related to Synaptic vesicle cycle and terpenoid skeleton biosynthesis pathway, such as ACAT, STX1A, and V-ATPase. The obtained results uniformly indicated that the neurotoxicity of M. aeruginosa seriously damaged the neurotransmitter conduction in the nervous system and brain information storage and transmission of zebrafish and makes it more susceptible to neurological diseases. Our study provides a new perspective on the neurotoxicity risk of cyanobacterial blooms.