Azithromycin is a poorly water-soluble drug with a lower dissolution rate which resulted in poor bioavailability after oral administration. The aim of this study was to enhance Azithromycin dissolution by a solid dispersion (SD) using solvent evaporation and supercritical fluid based on solvent-anti-solvent technique. Solid dispersions of Azithromycin were prepared with various concentrations of PEG 6000, Sorbitol and Poloxamer 188, SLS (in ternary systems). All samples were studied for the drug solubility. The formulations were also characterized by IR, DSC, XRD and SEM. The solubility and dissolution rate were remarkably improved in case of most SDs prepared with of PEG 6000 (in binary systems, 1:6 ratio) and both surfactants (ternary systems) compared to the related PMs and pure Azithromycin. But the best result was obtained in the dispersion (Azithromycin:PEG 6000:SLS) with a weight ratio of (1:4:2). SAS-SCF processes were signs of less crystallinity of the drug due to the transformation of its crystalline stat into amorphous state. The analysis of dissolution data indicated that enhanced drug dissolution can be achieved where the SDs obtained in the supercritical fluid process was consisted of PEG 6000 and SLS. The dissolution rate and solubility of Azithromycin improved significantly with PEG 6000 and SLS utilizing SAS-supercritical fluid.