Bioactive surfaces play a pivotal role in biomedical applications by enabling precise biological interactions through immobilized functional molecules. However, their performance is often hindered by nonspecific protein adsorption and cell adhesion. Antifouling polymer coatings have emerged as an effective solution, creating hydration barriers to preserve functionality and reduce biofouling. This review provides an overview of the recent advances in the development of antifouling polymer coatings for bioactive surfaces, with particular focus on nonionic polymers, such as polyethylene glycol (PEG), and zwitterionic polymers like poly(2-methacryloyloxyethyl phosphorylcholine) (PMPC). Among them, zwitterionic polymers, with their unique charge-balanced structures, exhibit exceptional hydration, protein resistance, and stability, making them particularly promising for biomedical applications. In addition, key applications of these bioactive surfaces, including their use in anticoagulant materials, antibacterial coatings, and biosensor interfaces, are also discussed. The discussion concludes with an address of the field's challenges and future directions, highlighting the need for innovative materials that balance antifouling properties, biocompatibility, and long-term stability for both clinical and industrial use. This review aims to review the latest advancements in antifouling polymer coatings for bioactive surfaces and provide insights into optimizing multifunctional bioactive surfaces to meet the evolving and dynamic demands of the biomedical field.