Phase change materials that can absorb or release large amounts of heat during phase transition, play a critical role in many important processes, including heat dissipation, thermal energy storage, and solar energy utilization. In general, phase change materials are usually encapsulated in passive modules to provide assurance for energy management. The shape and mechanical changes of these materials are greatly ignored. An emerging class of phase change materials, liquid metals (LMs) have attracted significant interest beyond thermal management, including in transformable robots, flexible electronics, soft actuators, and biomedicine. Interestingly, the melting point of LM is highly tunable around body temperature, allowing it to experience considerable stiffness change when interacting with human organisms during solid–liquid change, which brings about novel phenomena, applied technologies, and therapeutic methods, such as mechanical destruction of tumors, neural electrode implantation technique, and embolization therapy. This review focuses on the technology, regulation, and application of the phase change process along with diverse changes of LM to facilitate emerging biomedical applications based on the influences of mechanical stiffness change and versatile regulation strategies. Typical applications will also be categorized and summarized. Lastly, the advantages and challenges of using the unique and reversible process for biomedicine will be discussed.