This paper is devoted to the interfacial aspects of the intraocular behavior, migration and distribution of commonly injected ophthalmic drugs in eyes filled with medical-grade 1300 cSt silicone oil used as a retinal tamponade agent. Novel in vitro and ex vivo models were created for studying the physical properties of the retinal surface and interfacial spreading of the ophthalmic drugs over retinas. In vitro model experiments showed that the droplets of all tested drugs sank rapidly in the silicone oil to contact with the plasma-treated glass and then rapidly spread over the glass surface. In the ex vivo model, the migration phase was followed by contact with and rapid spread/absorption by the retinal interface. The wetting behavior of drugs under contact with the glass substrate and retinas was similar. The characteristic timescales of drug spreading, controlled by the viscous dissipation, were close. All tested drugs migrated to the retinal surface and rapidly spread across the retinal surface. This suggests that intravitreal drugs might be used effectively in eyes filled with silicone oil tamponade, as they rapidly migrate to and spread over the retinal surface.