High-entropy layered hydroxides (HELHs), an emerging frontier in entropy-stabilized materials derived from layered double hydroxides (LDHs), have captivated attention with their unparalleled tunability, thermodynamic stability, and electrochemical performance. The integration of the high-entropy concept into LDHs empowers HELHs to surmount the constraints of conventional materials through compositional diversity, structurally disordered configurations, and synergistic multi-element interactions. This review systematically embarks on their synthesis methodologies, functional mechanisms, and applications in energy conversion/storage and biomedicine. Advanced synthesis strategies, such as plasma-assisted hydrothermal methods, facilitate precise control over HELH architectures while supporting scalable production. HELHs demonstrate superior electrochemical performance in critical reactions, including oxygen evolution reaction, water oxidation, hydrogen evolution, and glucose electrooxidation. Future directions encompass integrating in situ characterization with simulations, leveraging machine learning for composition screening, and expanding HELHs application through interdisciplinary collaborations. This work establishes a comprehensive roadmap for advancing HELHs as next-generation multifunctional platforms for sustainable energy and biomedical technologies.