Neurodegenerative disorders represent a significant burden on global health and are characterized by progressive deterioration of neurons, which leads to cognitive and motor dysfunction. Understanding the mechanisms underlying neuronal demise is crucial for developing effective therapeutic strategies. Neuronal damage often stems from the interplay of multiple factors, including oxidative stress, excitotoxicity, protein misfolding, mitochondrial dysfunction, neuroinflammation, and impaired neurotrophic support. Several key signaling pathways involved in the regulation of these factors are NADPH oxidase, ionotropic glutamate receptors such as N-methyl-D-aspartate (NMDA) receptors and α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors, nuclear factor kappa B (NF-κB), mitogen-activated protein kinase (MAPK) pathways, receptor tyrosine kinases such as Trk receptors and the downstream phosphoinositide 3-kinase (PI3K)/Akt, and unfolded protein response (UPR). Understanding the intricate crosstalk between these pathways is essential to develop targeted therapeutic interventions aimed at halting or slowing neurodegeneration. Emerging therapeutic strategies include antioxidant therapies, modulators of excitotoxicity, proteostasis regulators, mitochondrial enhancers, anti-inflammatory agents, and neurotrophic factors. This chapter explores the complex pathways underlying neuronal damage and dysfunction, with a focus on the critical molecular and cellular mechanisms involved. A deeper understanding of these processes holds promise for the development of innovative therapeutic strategies aimed at mitigating neurodegeneration and improving patient outcomes