As one of the important types of two-dimensional materials, layered double hydroxides (LDHs) have been widely used in the biomedical field as carriers for drug delivery. In this case, we propose a facile synthetic method for preparing LDH-based self-assembly structures via a metal ions-mediated zeolitic imidazolate framework-8 (ZIF-8) transformation process. The as-made hierarchical porous ZIF-8@LDHs core–shell structures and porous cages of LDHs (PC-LDHs) in drug delivery systems are used to study the loading and release of small molecular weight drugs such as doxorubicin hydrochloride (DOX) and 5-fluorouracil (5-FU). The intrinsic properties and assembly structures of both carriers are investigated in depth for their impact on slow drug release. Finally, PC-LDHs outperform ZIF-8@LDHs core–shell structures in terms of drug delivery performance under various conditions, indicating that LDH nanosheets would play a decisive role in the drug delivery process. In the drug release system, scattered LDH nanosheets with smaller sizes than their assemblies are gradually produced, allowing nanodrugs to enter cancer tissues more easily across biological barriers. This study provides the preliminary preparation for an LDH-based nanomedicine platform in the field of cancer therapy.