DEC-205 receptor-mediated dendritic cells (DC) targeting nanoliposomes is a promising delivery system in eliciting an immune response against pathogens. When this delivery system carries both antigen and immunomodulator, it can effectively regulate the DC function as well as the initial T cell response. To maximize the desired therapeutic effects of Eucommia ulmoides Oliv. polysaccharides (EUPS), and induce an efficient humoral and cellular immune response against an antigen, we encapsulated the OVA and EUPS in long-circling nanoliposomes and conjugated it with anti-DEC-205 receptor antibody to obtain a DEC-205-targeted nanoliposomes (anti-DEC-205-EUPS-OVA-LPSM). The physicochemical properties and immune-modulating effects were investigated in vitro and in vivo by a series of the experiment to evaluate the targeting efficiency of anti-DEC-205-EUPS-OVA-LPSM. In vitro, anti-DEC-205-EUPS-OVA-LPSM (160 μg mL−1) could enhance DCs proliferation and increase their phagocytic efficiency. In vivo anti-DEC-205-EUPS-OVA-LPSM remarkably promoted the OVA-specific IgG and IgG isotypes levels, enhanced the splenocyte proliferation, and induced the NK cell and CTL cytotoxicity. Besides, the anti-DEC-205-EUPS-OVA-LPSM enhanced the maturation of DCs. These findings suggest that the DEC-205 receptor antibody-conjugated EUPS nanoliposome can act as an efficient antigen delivery system to enhance the cellular and humoral immune response by promoting DC maturation. This indicates that the anti-DEC-205-EUPS-OVA-LPSM has significant potential as an immune-enhancing agent and antigen delivery system.