[Display omitted] Adequate stabilization is essential for marketed protein-based biopharmaceutical formulations to withstand the various stresses that can be exerted during the pre- and post-manufacturing processes. Therefore, a suitable choice of excipient is a significant step in the manufacturing of such delicate products. Histidine, an essential amino acid, has been extensively used in protein-based biopharmaceutical formulations. The physicochemical properties of histidine are unique among amino acids and could afford multifaceted benefits to protein-based biopharmaceutical formulations. With a pKa of approximately 6.0 at the side chain, histidine has been primarily used as a buffering agent, especially for pH 5.5–6.5. Additionally, histidine exhibited several affirmative properties similar to those of carbohydrates (e.g., sucrose and trehalose) and could therefore be considered to be an alternative approach to established protein-based formulation strategies. The current review describes the general physicochemical properties of histidine, lists all commercial histidine-containing protein-based biopharmaceutical products, and discusses a brief outline of the existing research focused on the versatile applications of histidine, which can act as a buffering agent, stabilizer, cryo-/lyo-protectant, antioxidant, viscosity reducer, and solubilizing agent. The interaction between histidine and proteins in protein-based biopharmaceutical formulations, such as the Donnan effect during diafiltration of monoclonal antibody solutions and the degradation of polysorbates in histidine buffer, has also been discussed. As the first review of histidine in protein biopharmaceuticals, it helps to deepen our understanding of the opportunities and challenges associated with histidine as an excipient for protein-based biopharmaceutical formulations. [ABSTRACT FROM AUTHOR]