Drug discovery and development for Alzheimer’s disease (AD) are complex and challenging due to the higher failure rate in the drug development process. The overproduction and deposition of Aβ senile plaque and intracellular neurofibrillary tangle (NFT) formation are well-recognized diagnostic hallmarks of AD. Numerous transgenic models of Alzheimer’s disease have restrictions on cost-effectiveness and time in the preclinical setup. Zebrafish has emerged as an excellent complementary model for neurodegenerative research due to simpler organisms with robust, clearly visible behavior forms. Glutaminergic and cholinergic pathways responsible for learning and memory are present in zebrafish and actively participate in the transmission process. Therefore, it is imperative to study neurotoxic agents’ mechanisms that induce dysfunction of memory, learning, and neurons in the zebrafish. This review illustrates the in-depth molecular mechanism of several neurotoxic agents such as okadaic acid, cigarette smoke extract, and metals to produce cognitive deficits or neurodegeneration similar to mammals. These updates would determine an ideal and effective neurotoxic agent for producing AD pathophysiology in the zebrafish brain for preclinical screening.