Berberine is a natural compound found in several medicinal plants used for centuries in Asian countries, particularly in China and India. Chemically, berberine is a quaternary benzylisoquinoline alkaloid and its use in preclinical studies has shown a diversity of beneficial effects in models of human diseases including cancer, type 2 diabetes, heart disease, depression, obesity, epilepsy, and neurodegenerative diseases. Berberine exhibits its effects through modulating different cellular mechanisms resulting in decreased oxidative stress, inhibition of proinflammatory cytokines and angiogenesis, increased apoptosis, decreased metastasis, among other effects. Berberine modulates several intracellular signaling cascades including the PI3K/AKT/mTOR pathway, which, under homeostatic conditions, is involved in many processes including angiogenesis, apoptosis, cell migration, and proliferation, but under pathological conditions, overactivation or aberrant activation is associated with several human diseases such as those mentioned above and several neurodegenerative diseases such as Alzheimer’s and Parkinson’s disease. This chapter aims to analyze the interaction of berberine with the PI3K/AKT/mTOR pathway in two of the most common neurodegenerative illnesses, Alzheimer’s disease and Parkinson’s disease.