Protein modification/immobilization has been introduced as a large toolbox for creating a myriad of engineered proteins with profound implications for various scientific and industrial applications. Proteins immobilization techniques are generally performed through protein fixation in/to heterogeneous materials or via inter cross-linking of protein molecules, enabling the development of biocatalysts, biosensors, and drug delivery systems. On the other hand, chemical modification of proteins offers tailored changes in their functionality, enhances protein performance, extends their shelf life, and enables their specific binding interactions. The choice of immobilization or modification technique depends on the significance of various factors for the final product. Chemical coupling methods that create covalent bonds are commonly used for both proposes. Multi-component reactions are particularly effective because they operate under mild conditions to maintain protein functionality while simultaneously introducing multiple functional groups. This review provides an overview of multi-component reactions employed for the immobilization and modification of proteins.