Alzheimer’s, Parkinson’s, Huntington’s, multiple sclerosis, and other associated brain illnesses are largely caused by neurodegeneration. Their intricate pathophysiology frequently involves mitochondrial dysfunctions, misfolded polypeptide negativity, demyelination, genetic and neurochemical deficiencies, and genetic and neurochemical deficits. Neurodegenerative illnesses often show evolutionarily conserved pathways across species albeit varied in particular underlying causes. Human brain pathology has some similarities compared to the zebrafish’s central nervous system. In this chapter, we examine the role of zebrafish models in simulating the most prevalent human and animal neurodegenerative conditions. We discuss various computational models used for the neurodegenerative diseases. We also highlight how these fish models can help further understand the genetic, neurochemical, neuroanatomical, and behavioural pathogenic mechanisms.