Polyhedral oligomeric silsesquioxane (POSS) is a 3D, cage‐like nanoparticle with an inorganic Si–O–Si core and eight tunable corner functional groups. Its well‐defined structure grants it distinctive physical, chemical, and biological properties and has been widely used for preparing high‐performance materials. Recently, click chemistry has enabled the synthesis of various functional POSS‐based materials for diverse biomedical applications. This article reviews the recent applications of POSS‐based materials in the biomedical field, including cancer treatment, tissue engineering, antibacterial use, and biomedical imaging. Representative examples are discussed in detail. Among the various POSS‐based applications, cancer treatment and tissue engineering are the most important. Finally, this review presents the current limitations of POSS‐based materials and provides guidance for future research.