Didanosine is an anti-retroviral drug which helpful in preventing human immunodeficiency virus (HIV) from multiplication in the body. This drug has a relatively short half-life and low absolute bioavailability and requires frequent dosing. So to avoid this frequent dosing and to improve the patient’s compliance, the development of sustained-release tablets is necessary. Natural gums and resins play an important role in retarding drug release. Didanosine extended-release matrix formulations developed with wet granulation using gum kondagogu, guar gum, gum olibanum, and olibanum resin, and evaluated for pre and post-compression parameters. The outcome of all evaluation tests is reached IP specifications. Formulations with kondagogu F1-F3 failed to extend the drug release. F4-F6 was formulated with gum kondagogu and guar gum, in which F4 prolonged the release up to 12 hours with 98.23%. The formulations F7 with olibanum resin release 96.13%, and F10 with gum olibanum releases 93.15% drug at the end of 12 hours. The conclusion from the study was that natural polymers could be used to enhance drug release for an extended period.