Recent advancements in bioengineering and medical devices have been greatly influenced and dominated by synthetic polymers, particularly polyurethanes (PUs). PUs offer customizable mechanical properties and long‐term stability, but their inherent hydrophobic nature poses challenges in practically biological application processes, such as interface high friction, strong protein adsorption, and thrombosis. To address these issues, surface modifications of PUs for generating functionally hydrophilic layers have received widespread attention, but the durability of generated surface functionality is poor due to irreversible mechanical wear or biodegradation. As a result, numerous researchers have investigated bulk modification techniques to incorporate zwitterionic polymers or groups onto the main or side chains of PUs, thereby improving their hydrophilicity and biocompatibility. This comprehensive review presents an extensive overview of notable zwitterionic PUs (ZPUs), including those based on phosphorylcholine, sulfobetaine, and carboxybetaine. The review explores their wide range of biomedical applications, from blood‐contacting devices to antibacterial coatings, fouling‐resistant marine coatings, separation membranes, lubricated surfaces, and shape memory and self‐healing materials. Lastly, the review summarizes the challenges and future prospects of ZPUs in biological applications.