Hydrogels are three-dimensional networks of hydrophilic polymers that have garnered significant attention as wound-healing materials. Many synthetic hydrogels are fabricated using a radical polymerization approach that requires an initiator molecule that is often photo- or thermosensitive. Initiator-free hydrogels are an emerging area of research that focuses on hydrogel fabrication that occurs in the absence of an initiator or cross-linker molecule, making these hydrogels highly relevant in tissue engineering and regenerative medicine due to their excellent cytocompatibility and ease of scale-up. Here we present on the development of initiator-free zwitterionic hydrogels that photopolymerize without any initiator or cross-linker while under cytocompatible conditions. The hydrogels exhibit a wide range of mechanical characteristics that are dependent on their polymer composition. They resist nonspecific protein adsorption and exhibit a sustained release of proteins and small molecules. Additionally, these self-initiated hydrogels significantly mitigate inflammatory macrophage activation in vitro. Overall, the development of self-initiated photopolymerized zwitterionic hydrogels offers significant progress in the fields of biomaterials and materials science.