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Simple Summary: Numerous findings demonstrate that the central nervous system and the peripheral organs and tissues communicate in physiological and pathological conditions thanks to the exchange of signaling molecules transported via blood, cerebrospinal fluid, and lymph. Extracellular vesicles, which can cross tissue barriers, including the blood–brain barrier, play a key role in this bidirectional communication by safely delivering these molecules, including proteins, lipids, and nucleic acids such as microRNAs (miRNAs). In particular, the latter involved in the post-transcriptional regulation of gene expression can alter recipient cells' functions and orchestrate their behavior in response to different biological events. Thus, elucidating the role played by EVs-delivered miRNAs in brain–periphery communication could offer valuable insights for advancing the treatment and management of neurological and systemic diseases. Bidirectional communication between the central nervous system (CNS) and peripheral organs and tissue has been widely documented in physiological and pathological conditions. This communication relies on the bilateral transmission of signaling molecules and substances that circulate throughout the body and reach their target site(s) via the blood and other biological fluids (e.g., the cerebrospinal fluid, the lymph). One of the mechanisms by which these molecular messengers are exchanged is through the secretion of extracellular vesicles (EVs). EVs are known to mediate cell-to-cell communication by delivering biological molecules, including nucleic acids, proteins, lipids, and various other bioactive regulators. Moreover, EVs can cross the blood–brain barrier (BBB), enabling direct communication between the periphery and the brain. In particular, the delivery of microRNAs (miRNAs) can modulate the expression profiles of recipient cells, thereby influencing their functions. This review synthesizes current findings about the brain–periphery cross-talk mediated by EVs-delivered miRNAs. Although this mechanism has been definitively shown in a few cases, much evidence indirectly indicates that it could mediate brain–peripherical organs/tissue communication, especially in pathological conditions. Therefore, understanding this process could provide valuable insights for the treatment and management of neurological and systemic diseases. [ABSTRACT FROM AUTHOR]