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COVID-19 is an infectious disease caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), which led to a pandemic started in Wuhan, China, in 2019. The rapid spread of the disease in the world, unprecedented mortality rate, and lack of definitive treatment for the disease have led to a global effort to develop effective vaccines as well as new therapeutic interventions. Immune cells activation with excessive inflammation is an important pathophysiological feature of COVID-19 that may impair the various organs functions. Accordingly, these could cause dysfunction in the brain with some symptoms such as respiratory failure, headache, impaired consciousness, olfactory and taste disorders, and severe neurological disorders such as encephalitis. It was found that there is a two-way communication between the immune system and the nervous system through classical neurotransmitters, hormones, and cytokines. Among neurotransmitters, serotonin plays important roles in the immune system and in regulating inflammatory responses by central and peripheral mechanisms. This article aimed to review the two-way relationship between the immune and the nervous systems by focusing on the serotonergic system and the emerging COVID-19 disease.