The aim of this study was to enhance the solubility of rosuvastatin (RST) calcium by developing β-cyclodextrin- g-poly(2-acrylamido-2-methylpropane sulfonic acid [AMPS]) hydrogel microparticles through aqueous free-radical polymerization technique. Prepared hydrogel microparticles were characterized for percent entrapment efficiency, solubility studies, Fourier transform infrared spectroscopy, differential scanning calorimetry, thermal gravimetric analysis, powder X-ray diffraction, scanning electron microscopy, zeta size and potential, swelling and release studies. Formulations (HS1–HS9) have shown entrapment efficiency between 83.50%±0.30% and 88.50%±0.25%, and optimum release was offered by formulation HS7 at both pH levels, ie, 1.2 (89%) and 7.4 (92%). The majority of microparticles had a particle size of less than 500 µm and zeta potential of −37 mV. Similarly, optimum solubility, ie, 10.66-fold, was determined at pH 6.8 as compared to pure RST calcium, ie, 7.30-fold. In vivo studies on fabricated hydrogel microparticulate system in comparison to pure drug were carried out, and better results regarding pharmacokinetic parameters were seen in the case of hydrogel microparticles. A potential approach for solubility enhancement of RST calcium and other hydrophobic moieties was successfully developed.