Microspheres have excellent sealing performances such as injectivity, bridging-off, deep migration, and deformation performances, but their plugging effects are limited by the fast swelling rate and poor viscoelasticity. In this study, we synthesized a novel modified microsphere with polymerizable surfactant monomers and cationic monomers. We investigated the influence factors on the swelling performance and rheological properties of the microspheres and explored the ways to improve the plugging performance of hydrophobic-associating microspheres. The association behaviors in aqueous media of poly(acrylamide-comethacry loyloxyethyl trimethyl ammonium chloride-co-n-dodecyl poly(etheroxy acrylate) P(AM-DMC-DEA) are proven to be mediated by the DEA content. Moreover, the hydrophobic association interaction has a strong effect on the performance of microspheres such as swelling properties, the rheological performance, and plugging properties. The swelling properties of microsphere studies exhibited the slow swelling rate. The rheological performance measurements showed significant improvements; yield stress, and creep compliance increased rapidly from 404 to 2060 Pa and 3.89 × 10 −4 to 1.41 × 10 −2 1/Pa, respectively, with DEA content in microspheres rising from 0.0% to 0.22%. The plugging properties of microspheres were enhanced by the slow swelling performance and good viscoelasticity.