The study focuses on the reactive extrusion of sodium caseinate by an enzymatic cross-linking of proteins in the extruder barrel. A co-rotating parallel intermeshing twin-screw extruder was used for the extrusion process of proteins without prior pelletizing. Feasible process conditions were identified and transferred to a process window which allow a covalent cross-linking of sodium caseinate via the enzyme microbial transglutaminase (MTG) and an incorporation of crystalline materials in the protein matrix. Transparent, homogenous and smooth structured sodium caseinate films were produced and characterized. The mechanical properties of sodium caseinate films (non-cross-linked, cross-linked and crystallized) were determined and correlated to important process conditions. An enzymatic cross-linking leads to a significant increase of the tensile strength of the films (up to 85%) while the elongation did not deteriorate. Furthermore, the relationship between the residence time and the mechanical properties shows that residence times between 100 and 120 s offer maximum mechanical performance due to longer reaction times leading to higher cross-linking densities. It was found additionally that inner-film crystallized sodium caseinate films show significant higher elongation values. In this regard, crystalline structures (size, shape and distribution of potassium nitrate crystals) were identified and correlated to the tensile properties of the films. The synergistic effect of crystalline additives and cross-linking enhances physical and functional properties of protein films and offer additional product benefits. By combining application-oriented bio-based product design with an efficient large-scale production process, new advanced materials and products for many fields of applications could be developed and produced.