The primary regulators of neuronal proliferation, differentiation, and survival are neurotransmitters (NT). Numerous physical, psychological, and neurodegenerative diseases are brought on by the impairment of brain physiological functions due to aberrant NT levels. Neurodegenerative symptoms have been linked to deficits in several NTs. While cholinergic and glutamatergic impairments have been connected to cognitive decline in Alzheimer’s, monoamine neurotransmission changes have been intimately linked to neuropsychiatric symptoms. Parkinson’s disease (PD) results mainly from the death of dopaminergic neurons, majorly in the substantia nigra pars compacta, which results in dopamine insufficiency manifested in movement dysfunction. Huntington’s disease, manifested via cognitive and motor changes, is primarily described by altered levels of dopamine, glutamate, adenosine, and acetylcholine. Amyotrophic lateral sclerosis (ALS) covers a variety of symptoms, such as severe metabolic dysregulation, muscular atrophy, paralysis, and motor neuron degeneration, where increased glutamate levels and accompanying neurotoxicity are suggested mechanisms. Modulating neurotransmitter transporters (NTT), which regulate brain NT homeostasis, can be a possible therapeutic approach in certain neurodegenerative illnesses. Also, the studies indicate a nexus between anomalous neuronal metabolism and neurodegeneration. The high energy requirements of the brain make it particularly vulnerable to mitochondrial damage. Most neurodegenerative disorders exhibit aberrant mitochondrial morphology. For cellular energy needs, mitochondria synthesize ATP, and reactive oxygen species (ROS) are toxic byproducts produced during impaired oxidative phosphorylation in mitochondria. The buildup of intracellular ROS can damage mtDNA and nuclear DNA, possibly leading to many age-related disease states. In addition to its evident role in energy homeostasis, mitochondrial dysfunction also interferes with calcium homeostasis, which can have severe consequences in neuropathologies. For instance, in Alzheimer’s disease, defects in calcium homeostasis can result in intracellular calcium accumulation, glutamate-induced excitotoxicity, and neuronal loss. In this chapter, we have discussed the role of NTs and mitochondria in the pathogenesis of common neurodegenerative disorders like Parkinson’s disease, Alzheimer’s disease, amyotrophic lateral sclerosis, and Huntington’s disease.