The growing environmental concern with the inappropriate disposal of conventional plastics has driven the development of eco-friendly food packaging. However, the intrinsic characteristics of polymers of a renewable origin, e.g., poor mechanical properties, continue to render their practical application difficult. For this, the present work studied the influence of ionic strength (IS) from 0 to 500 mM to modulate the physicochemical properties of methylcellulose (MC). Moreover, for protection against biological risks, Nisin-Z was incorporated into MC’s polymeric matrices, providing an active function. The incorporation of salts (LiCl and MgCl2) promoted an increase in the equilibrium moisture content in the polymer matrix, which in turn acted as a plasticizing agent. In this way, films with a hydrophobic surface (98°), high true strain (85%), and low stiffness (1.6 mPa) can be manufactured by addition of salts, modulating the IS to 500 mM. Furthermore, films with an IS of 500 mM, established with LiCl, catalyzed antibacterial activity against E. coli, conferring synergism and extending protection against biological hazards. Therefore, we demonstrated that the IS control of MC dispersion presents a new alternative to achieve films with the synergism of antibacterial activity against Gram-negative bacteria in addition to flexibility, elasticity, and hydrophobicity required in various applications in food packaging.