Azithromycin, a macrolide antibiotics, is one of the frequently used drugs in the children and elder. However, due to these population difficulty in swallowing and inefficient absorption, and azithromycin inherent poor solubility, bitter taste, and instability in the stomach acidic condition, it is a challenge to reach high oral bioavailability of this drug. To overcome these issues, we developed and characterized the effervescent granules containing azithromycin solid dispersion. Firstly, the solid dispersion was prepared, employing both wet grinding and solvent evaporation methods, with different types/amounts of polymers. The optimal solid dispersion with β-cyclodextrin at a drug:polymer ratio of 1:2 (w/w), prepared by the solvent evaporation method, significantly enhanced the azithromycin solubility 4-fold compared to the free drug, improved its bitterness from “bitter” to “normal”, possessed intermolecular bonding between the drug and polymer, and transformed the azithromycin molecules from crystalline to amorphous state. Secondly, the effervescent granules incorporating the solid dispersion were formulated with varied excipients of sweeteners, gas-generators, pH modulators, and glidants/lubricants. The optimal formula satisfied all the properties stated in the Vietnamese Pharmacopoeia. In summary, the final effervescent granules product could be further investigated in in-vivo and in clinical settings to become a potential azithromycin delivery system with high bioavailability for the children and elder.