A novel sericin-dextran conjugate (SDC) and self-assembled microparticles has been prepared for improving solubility of atazanavir. Microparticles of SDC were assembled by the reprecipitation method. The size and morphology of SDC microparticles could be adjusted by the concentration and solvents. Low concentration was conducive to the preparation of microspheres. Heterogeneous microspheres could be prepared in ethanol with the range of 85–390 nm, and hollow mesoporous microspheres in propanol with an average particle size of 2.5–22 µm. The aqueous solubility of atazanavir was improved to 2.22 mg/mL in buffer solutions at pH 2.0 and 1.65 mg/mL at pH 7.4 by SDC microspheres. In vitro release of atazanavir from hollow microspheres of SDC exhibited a slower release, had the lowest linear cumulative release in basic buffer (pH 8.0), and the most rapid double exponential diphase kinetic cumulative release in acid buffer (pH 2.0).