Biomaterial coatings and films can prevent premature failure and enhance the performance of chronically implanted medical devices. However, current hydrophilic polymer coatings and films have significant drawbacks, including swelling and delamination. To address these issues, hydroxyethyl cellulose is modified with thioether groups to generate an oxidation‐responsive polymer, HECMTP. HECMTP readily dissolves in green solvents and can be fabricated as coatings or films with tunable thicknesses. HECMTP coatings effectively scavenge hydrogen peroxide, resulting in the conversion of thioether groups to sulfoxide groups on the polymer chain. Oxidation‐driven, hydrophobic‐to‐hydrophilic transitions that are isolated to the surface of HECMTP coatings under physiologically relevant conditions increase wettability, decrease stiffness, and reduce protein adsorption to generate a non‐fouling interface with minimal coating delamination or swelling. HECMTP can be used in diverse optical applications and permits oxidation‐responsive, controlled drug release. HECMTP films are non‐resorbable in vivo and evoke minimal foreign body responses. These results highlight the versatility of HECMTP and support its incorporation into chronically implanted medical devices.