The hydrophobic modification of sodium alginate was realized by direct grafting with glycolic acid. The products, polyglycolic acid grafting from sodium alginate (Alg-g-PGA), self-assembled into nanoparticles of 200-250 nm in diameter through the interaction of hydrophobic PGA segments in the aqueous solution. Alg-g-PGA nanoparticles were cross-linked into hydrogel microspheres by calcium chloride, which was used as drug delivery vehicles for controlled release. The results of drug (ibuprofen) release model exhibited high drug loading rate and prolonged drug release speed of the Alg-g-PGA gel microspheres. The one-step method of synthesizing hydrophobically modified sodium alginate processes simple operation, mild condition, and low-cost raw material, resulting in its wide application of biological medicine in the future.