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Objective: Losartan potassium is one of the widely prescribed antihypertensive drugs administered orally and its extended-release tablet formulations are essentially required for the long-acting effect at reduced dosage frequency. The present research was aimed for the development and optimization of an extended-release tablet of losartan potassium, exploring natural gums, i.e., xanthan gum and guar gum as drug release modifiers. Methods: The tablet formulation was prepared by wet granulation method and the formulation optimization was done by D-optimal mixture design using Design Expert® software. The independent variables studied were xanthan gum (X1), guar gum (X2) and lactose (X3) taking various combinations of the total amount of gum and ratio of xanthan gum to guar gum under the given constraint range. The dependent (response) variables studied were % drug release in 1h (Y1), 4h (Y2), 7h (Y3) and 10h (Y4). The developed tablets were evaluated for physical properties, i.e., hardness, friability, weight variation as well as the in vitro drug release profiles. For optimization studies, the polynomial equations and response surface plots were generated and the optimized formulation was selected on the basis of maximum desirability value. Results: The developed tablet formulation was found to possess all physical properties within the desired range and showed sustained release profile with ~80% drug release in 10 h duration. The model fitting studies demonstrated best fit in the zero-order model and the slope value of Korsmeyer–Peppas plot was ˃0.89, suggesting case II transport as a drug release mechanism. Conclusion: The findings suggested that natural gums-based matrix tablets of losartan could be successfully developed and natural gums can be explored as platform technology as release retardants and in the development of sustained-release matrix tablets of other drugs.