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The endophilin protein family comprises a group of evolutionarily highly conserved Bin-Amphiphysin-Rvs (BAR) domain proteins that play key roles in cell membrane morphogenesis, endocytic trafficking, and organelle dynamics. The human endophilin family includes five main members, encoded by the genes SH3GL2 (endophilin A1), SH3GL1 (endophilin A2), SH3GL3 (endophilin A3), SH3GLB1 (endophilin B1), and SH3GLB2 (endophilin B2). Notably, SH3GLB1 gives rise to functionally distinct splice variants, including the ubiquitously expressed B1a and the neuron-enriched B1b/c, which play critical, opposing roles in conditions such as Alzheimer disease (AD). These isoforms perform distinct, often opposing functions in disease pathogenesis via specific molecular mechanisms. For instance, endophilin A1 acts as a tumor suppressor; its gene, SH3GL2, is frequently deleted or downregulated in cancers such as non-small cell lung cancer, and its loss promotes tumor progression by sustaining epidermal growth factor receptor (EGFR) signaling. Conversely, endophilin A2 drives cancer metastasis. In AD, endophilin A1 expression is significantly elevated, exacerbating synaptic dysfunction, while neuron-specific endophilin B1 isoforms are decreased, worsening amyloid pathology. The regulation of endophilins involves intricate networks, including post-transcriptional control by microRNAs (e.g., miR-330 targeting SH3GL2 in glioblastoma) and post-translational modifications. This review provides a comprehensive overview of the structural characteristics and regulation of expression and activity. It delineates the molecular mechanisms by which their dysfunction contributes to disease pathogenesis, aiming to provide new insights into these multifaceted proteins in health and disease.