Conventional biomaterial is frequently used in the biomedical sector for various therapies, imaging, treatment, and theranostic functions. However, their properties are fixed to meet certain applications. Smart materials respond in a controllable and reversible way, modifying some of their properties because of external stimuli. However, protein-based smart materials allow modular protein domains with different functionalities and responsive behaviours to be easily combined. Wherein, these “smart” behaviours can be tuned by amino acid identity and sequence. This review aims to give an insight into the design of smart materials, mainly protein-based piezoelectric materials, shape-memory materials, and hydrogels, as well as highlight the current progress and challenges of protein-based smart materials in tissue engineering. These materials have demonstrated outstanding regeneration of neural, skin, cartilage, bone, and cardiac tissues with great stimuli-responsive properties, biocompatibility, biodegradability, and biofunctionality.