Background: The oral approach to medication administration remains highly preferred due to its convenience and improved patient compliance compared to parenteral methods. Oral controlled-delivery systems maintain consistent therapeutic drug levels, thereby maximizing safety and reducing side effects. Among these, matrix sustained-release tablets are highly favored for their manufacturing simplicity, cost-effectiveness, and resistance to dose dumping. Objective: This research aimed to develop and optimize sustained-release matrix tablets of Diltiazem Hydrochloride—a calcium channel blocker for hypertension and angina characterized by a short elimination half-life (3.5 hours) and low bioavailability (30–40%) due to extensive first-pass metabolism—using the natural biopolymers Tamarind gum and Cassia roxburghii gum as release modifiers. Methods: Preformulation Fourier Transform Infrared (FTIR) spectroscopy was performed to evaluate drug-polymer compatibility. Powder blends were characterized for flow properties prior to compression. The formulated tablets were evaluated for physical parameters per official Indian Pharmacopoeia (IP) standards, alongside in-vitro dissolution testing. Results: FTIR spectra revealed no chemical interactions between the drug and the natural gums. The powder blends exhibited favorable flow properties, with an angle of repose between 25° and 33° and a Carr's Index ranging from 9.0 to 19.0. All compressed tablets met IP specifications for hardness, thickness, friability, weight variation, and content uniformity. In-vitro drug release studies demonstrated that the optimized formulation, DH13, successfully prolonged drug release, achieving a maximum dissolution of 99.94% at 12 hours. Kinetic modeling indicated that the release mechanism strictly adhered to the Higuchi model, exhibiting a high correlation coefficient (R2 = 0.980). Furthermore, accelerated stability testing (40 °C±2°C 75 ± 5%) of the optimized DH13 batch over 30 days showed no significant changes in physical appearance, chemical content, or dissolution profiles. Conclusion: The study demonstrates that the optimized natural polymer-based matrix tablet (DH13) provides a robust, stable, and highly reproducible 12-hour sustained-release profile suitable for the effective oral administration of Diltiazem Hydrochloride.