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B lymphocytes play crucial roles in host immune responses by mediating humoral immunity via the production of various types of antibodies and also contribute to the pathogenesis of a wide range of inflammatory, autoimmune, and neoplastic disorders. Recently, considerable literature has grown around the naturally occurring compounds immunomodulatory potential. In this regard, berberine (BBR) is an isoquinoline alkaloid with unique pharmacological actions including anti-inflammatory, anti-oxidant, anti-microbial, and anti-tumor activity, which arises from its polytrophic pharmacological and biochemical properties. Up to now, no previous study has investigated the immunomodulatory actions of BBR on B cells. Herewith, this review attempts to explore the immunomodulatory effects of BBR on B cells by gathering all evidence from research investigations. BBR has high potency to inhibit the activation, proliferation, and differentiation of pathological B cells, which is represented by the reduced number of antibody-producing B cells and the production of IgE (allergies) and IgG/IgA autoantibodies (autoimmune and inflammatory disorders). The molecular mechanisms by which BBR play its modulatory action are interacting with NF-κB, MAPK, JAK/STAT, and PI3K signaling pathways, along with the regulation of transcription factors such as STAT6, GATA3, and Blimp-1. Interestingly, BBR has stimulatory effects on B cells in infection via the augmentation of IgM, IgA, and IgG production. Notably, BBR and its derivatives exerts anti-tumor activities against B cell malignancies by inducing DNA damage, expression of proapoptotic proteins, cell cycle arrest, cell death, dysregulation of mitochondrial metabolism, reactive oxygen species (ROS), which are mainly mediated by modulating c-Myc/CD47 axis, ROS/JNK/DNA damage pathway, PIK3CG signaling cascade, and the expression of CDK4, CDK6, CyclinD1, CD19, CD69, Ki67, and Bcl-2. BBR also shows contradictory effects on the therapeutic efficacy of conventional anti-lymphoma therapies such as rituximab. Together these findings support that BBR could be considered as a promising natural agent for immunomodulation in pathologic conditions by targeting B cells.