Despite advances in medical treatments for severe trauma, it remains a critical condition associated with high mortality. During trauma, the release of endogenous damage-associated molecular patterns (DAMPs) can induce immune dysfunction, leading to sepsis or multiple organ dysfunction syndrome (MODS). Vaccines based on specific pathogen antigens and pathogen-associated molecular patterns (PAMPs) contribute largely to the prevention of communicable diseases through the induction of adaptive immune responses. Vaccines developed based on autologous molecules may also promote recovery from non-communicable diseases (NCDs) by eliciting appropriate immune responses, as recent clinical trials indicate. Developing new vaccines targeting DAMPs may be an effective pre-protective measure for trauma management. We describe the role of DAMPs in post-traumatic immune dysfunction and discuss the potential of harnessing them for trauma vaccine development as well as the risks and challenges.