Despite the exceptional physicochemical and morphological characteristics, the pristine layered double hydroxides (LDHs), or two-dimensional (2D) hydrotalcite clays, often suffer from various shortcomings in biomedicine, such as deprived thermal and chemical stabilities, acid-prone degradation, as well as lack of targeting ability, hampering their scale-up and subsequent clinical translation. Accordingly, diverse nanocomposites of LDHs have been fabricated by surface coating of organic species, impregnation of inorganic species, and generation of core-shell architectures, resulting in the complex state-of-the-art architectures. In this article, we initially emphasize various bothering limitations and the chemistry of these pristine LDHs, followed by discussions on the engineering strategies of different LDHs-based nanocomposites. Further, we give a detailed note on diverse LDH nanocomposites and their performance efficacy in various biomedical applications, such as drug delivery, bioimaging, biosensing, tissue engineering and cell patterning, deoxyribonucleic acid (DNA) extraction, as well as photoluminescence, highlighting the influence of various properties of installed supramolecular assemblies on their performance efficacy. In summary, we conclude with interesting perspectives concerning the lessons learned to date and the strategies to be followed to further advance their scale-up processing and applicability in medicine.