AbstractMost vaccines require several immunizations to induce robust immunity, and indeed, most SARS‐CoV‐2 vaccines require an initial two‐shot regimen followed by several boosters to maintain efficacy. Such a complex series of immunizations unfortunately increases the cost and complexity of populations‐scale vaccination and reduces overall compliance and vaccination rate. In a rapidly evolving pandemic affected by the spread of immune‐escaping variants, there is an urgent need to develop vaccines capable of providing robust and durable immunity. In this work, a single immunization SARS‐CoV‐2 subunit vaccine is developed that can rapidly generate potent, broad, and durable humoral immunity. Injectable polymer–nanoparticle (PNP) hydrogels are leveraged as a depot technology for the sustained delivery of a nanoparticle antigen (RND‐NP) displaying multiple copies of the SARS‐CoV‐2 receptor‐binding domain (RBD) and potent adjuvants including CpG and 3M‐052. Compared to a clinically relevant prime‐boost regimen with soluble vaccines formulated with CpG/alum or 3M‐052/alum adjuvants, PNP hydrogel vaccines more rapidly generated higher, broader, and more durable antibody responses. Additionally, these single‐immunization hydrogel‐based vaccines elicit potent and consistent neutralizing responses. Overall, it is shown that PNP hydrogels elicit improved anti‐COVID immune responses with only a single administration, demonstrating their potential as critical technologies to enhance overall pandemic readiness.