Squalene-based emulsion (SE) adjuvants like MF59 and AS03 are used in protein subunit vaccines against influenza virus (e.g., Fluad, Pandemrix, Arepanrix) and SARS-CoV-2 (e.g., Covifenz, SKYCovione). We demonstrate the critical role of uric acid (UA), a damage-associated molecular pattern (DAMP), in triggering immunogenicity by SE adjuvants. In mice, SE adjuvants elevated DAMP levels in draining lymph nodes. Strikingly, inhibition of UA synthesis reduced vaccine-induced innate immunity, subsequently impairing optimal antibody and T cell responses. In vivo treatment with UA crystals elicited partial adjuvant effects. In vitro stimulation with UA crystals augmented the activation of dendritic cells (DCs) and B cells and altered multiple pathways in these cells, including inflammation and antigen presentation in DCs and cell proliferation in B cells. In an influenza vaccine model, UA contributed to protection against influenza viral infection. These results demonstrate the importance of DAMPs, specifically the versatile role of UA in the immunogenicity of SE adjuvants, by regulating DCs and B cells