In this study, different ratios of mucin-grafted polyethylene-glycol-based microparticles were prepared and evaluated both in vitro and in vivo as carriers for the oral delivery of insulin. Characterization measurements showed that the insulin-loaded microparticles display irregular porosity and shape. The encapsulation efficiency and loading capacity of insulin were >82% and 18%, respectively. The release of insulin varied between 68% and 92% depending on the microparticle formulation. In particular, orally administered insulin-loaded microparticles resulted in a significant fall of blood glucose levels, as compared to insulin solution. Subcutaneous administration showed a faster, albeit not sustained, glucose fall within a short time as compared to the polymeric microparticle-based formulations. These results indicate the possible oral delivery of insulin using this combination of polymers.