The objective of the current research study was to formulate and evaluate a sustained-release linezolid tablet using the natural antibacterial polymer Aegle marmelos. The natural gum of Aegle marmelos is becoming increasingly used in pharmaceutical formulations as a beneficial medication with excipients. Natural-based plant materials are biocompatible, free of side effects, biodegradable, and economic. Therefore, in order to maintain the drug releases from the matrix system, Aegle marmelos fruit gum as a natural polymer and HPMC grade (K100M) as a synthetic polymer were used in the formulation of the linezolid matrix tablet. The formulation of sustained-release matrix tablets included the wet granulation technique. The formulated matrix tablets were evaluated in terms of weight variation, hardness, diameter, physical appearance, friability, thickness, and in vitro drug release. Each formulation’s matrix tablet passed the required physical assessment tests. The formulation analyses of the tablets’ dissolution showed sustained releases of drugs for up to 10–12 hours. Additionally, several polymer combinations and fillers were used to improve drug release factors using the 32 factorial design approach, drug release kinetics were optimized, and the antibacterial study was evaluated.