Telodendrimer specifically refers to a linear-dendritic copolymer containing a single monodendron or dendrimer and a linear segment attached at the “focal” point of the dendritic fragment. The well-defined chemical structure of telodendrimer allows for precise engineering of functionalities in telodendrimer for stable incorporation of therapeutic proteins via multivalent and hybrid interactions. The telodendrimer provides a versatile platform that enables (i) the encapsulation of proteins to form nanoparticles for tumor-targeted protein delivery by the enhanced permeability and retention effects, (ii) the formation of lipidoid-telodendrimer hybrid nanoparticles for intracellular delivery of truncated diphtheria toxin in brain tumor treatment, (iii) the structure-based nanocarrier design for insulin delivery towards effective control of blood glucose levels, and (iv) the detachable protection of protein-polycation nanocomplex for efficient intracellular protein delivery with reduced polycation-associated cytotoxicity and hemolytic activity, as well as eliminated aggregation and non-specific binding of polycations to other biomacromolecules. In this review, the telodendrimer-based protein delivery systems are summarized. The affinity-controlled protein encapsulation and the targeted and/or intracellular protein delivery for disease treatments by employing telodendrimer nanocarriers are discussed.