MXenes are a class of 2D transition metal carbides and nitrides (Mn+1XnT) that have attracted significant interest owing to their remarkable potential in various fields. The unique combination of their excellent electromagnetic, optical, mechanical, and physical properties have extended their applications to the biological realm as well. In particular, their ultra-thin layered structure holds specific promise for diverse biomedical applications. This comprehensive review explores the synthesis methods of MXene composites, alongside the biological and medical design strategies that have been employed for their surface engineering. This review delves into the interplay between these strategies and the resulting properties, biological activities, and unique effects at the nano-bio-interface. Furthermore, the latest advancements in MXene-based biomaterials and medicine are systematically summarized. Further discussion on MXene composites designed for various applications, including biosensors, antimicrobial agents, bioimaging, tissue engineering, and regenerative medicine, are also provided. Finally, with a focus on translating research results into real-world applications, this review addresses the current challenges and exciting future prospects of MXene composite-based biomaterials.