The gut-brain connection plays a critical role in the pathophysiology of numerous neurological disorders. This book chapter explores the role of the gut microbiome in this complex interaction through key mechanisms, including the endocrine, immune, and vagus nerve pathways and metabolic activities. Dysbiosis, a gut microbiota imbalance, contributes to neuroinflammation, altered neurotransmitter levels, and increased blood-brain barrier (BBB) permeability, which are associated with the development and progression of neurological conditions such as Alzheimer’s disease, Parkinson’s disease, anxiety, depression, and autism spectrum disorder. Gut microbiome-derived metabolites such as short-chain fatty acids (SCFAs), including butyrate, acetate, and propionate, are known to cross the BBB and modulate the neuroinflammatory pathways, synaptic plasticity, and cognitive functions. Additionally, microbial production of neurotransmitters like gamma-aminobutyric acid (GABA), serotonin, and dopamine directly affects CNS signaling, with implications in mood disorders and neurodegenerative diseases. Dysregulated gut microbiota can impair the gut-brain communication via the vagus nerve, which further contributes to neurodegenerative processes. The gut microbiome showed also significant impact on the pharmacokinetics and pharmacodynamics of neurological drugs. Emerging therapeutic strategies can include the development of tailored psychomicrobiotics, which aim to modulate the gut microbiome composition by enhancing the drug efficacy and restoration of neuroimmune homeostasis. Dietary interventions, including prebiotics and probiotics, are also proposed as adjunct therapies to modulate gut microbiota and improve brain health. Overall, the gut microbiome offers novel choices for next-generation treatments aimed at improving brain function and limiting disease progression.