The origin of life (OoL) has always been a mysterious and challenging topic that puzzles human beings. Clay minerals have unique properties and wide distribution in early Earth environments. They can not only adsorb biological small molecules to catalyze their polymerization, but play an active role in the formation and evolution of protocells. In this review, the research progress on the interactions of clay minerals with biomolecules and protocells complex structures in the field of the OoL based on chemical evolution theory is summarized. The types, structures and properties of clay minerals, biological molecules and protocell models related to the OoL are introduced in detail. The mechanism of interaction between clay minerals and biological molecules, the construction of protocells and the role of clay minerals in the formation, structure and stability of protocells are systematically described. Finally, the future research priorities and challenges in the field of OoL based on clay minerals, biomolecules and protocells are discussed. It is aspired that this review can further advance the exploration of the OoL from a new perspective, and can also bring some interesting findings and ideas to the interdisciplinary research of materials, biology, chemistry and other related disciplines.Clay minerals have a variety of interactions with small biomolecules, which can be used as structural and functional templates to promote the organic synthesis of biomolecules and the formation and evolution of protocells, playing a non‐negligible role in the field of the OoL.