Therapeutic ophthalmic contact lenses with prolonged drug release and improved bioavailability have been developed to circumvent tedious eye drop instillation. In this work, zwitterionic nanogels based on poly(sulfobetaine methacrylate) (PSBMA) were easily fabricated by one-step reflux-precipitation polymerization, with the advantages of being surfactant-free and morphology controlled. Then, the ophthalmic drug levofloxacin (LEV) was encapsulated into the nanogels. A set of contact lenses with varied nanogel-loading content was fabricated by the cast molding method, with the drug-loaded nanogels dispersed in pre-monomer solutions composed of 2-hydroxyethyl methacrylate (HEMA) and N-vinyl-2-pyrrolidone (NVP). The structure, surface morphology, water contact angle (WCA), equilibrium water content (EWC), transmittance, and mechanical properties of the contact lenses were subsequently investigated, and in vitro drug release and biocompatibility were further evaluated. As a result, the optimized contact lens with nanogel-loading content of 8 wt% could sustainably deliver LEV for ten days, with critical lens properties within the range of recommended values for commercial contact lenses. Moreover, cell viability assays revealed that the prepared contact lenses were cytocompatible, suggesting their significant potential as an alternative to traditional eye drops or ointment formulations for long-term oculopathy treatment.