To effectively control viral pandemics, a multifaceted approach incorporating diverse vaccination strategies may be imperative. Our study demonstrates that both mucosal and non-mucosal immunization of mice with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) subunit vaccine enriched with thymic stromal lymphopoietin (TSLP) results in potent vaccine-specific systemic IgG and IgG1 antibody responses, but only mucosal immunization can induce robust mucosal IgA antibody and neutralizing antibody against SARS-CoV-2 wild-type, Alpha B.1.1.7, and Delta B.1.617.2 variant strains. We found that the immune-enhancing effect of TSLP relies on promoting dendritic cell (DC) migration and activation, which in turn enhances the germinal center (GC) responses. Furthermore, intranasal administration of the TSLP-adjuvanted vaccine protected against challenges from both SARS-CoV-2 wild-type and Delta B.1.617.2 strains. Our findings offer valuable insights into the importance of TSLP as a critical mucosal adjuvant in enhancing mucosal adaptive immunity by modulating DC-GC crosstalk, hence enhancing vaccination effectiveness. IMPORTANCE: The current development and implementation of subunit vaccines in clinical practice encounter a number of challenges. The most significant difficulties are the scarcity of effective adjuvants and the fact that most vaccination programs rely on non-mucosal injections, which frequently fail to establish mucosal adaptive immunity and hence restrict the potential to protect against respiratory viral infections. Our research indicates that TSLP can effectively boost SARS-CoV-2 subunit vaccine-specific systemic and mucosal humoral immunity in mice after intranasal immunization, protecting them from SARS-CoV-2 wild-type and Delta variant infection. The mucosal adjuvant effects of TSLP depend on DC migration and activation, which boosts germinal center responses. Therefore, supplementation of mucosal subunit vaccines with TSLP should be considered in vaccine development, particularly when the vaccine is administered to children and the elderly. Our findings provide new evidence for the development of mucosal adjuvants for infectious diseases, potentially facilitating future vaccine development.