To help design needed new vaccines for pneumonic plague, we targeted the Yersinia pestis LcrV protein directly to CD8α⁺ DEC‐205⁺ or CD8α⁻ DCIR2⁺ DC along with a clinically feasible adjuvant, poly IC. By studying Y. pestis in mice, we could evaluate the capacity of this targeting approach to protect against a human pathogen. The DEC‐targeted LcrV induced polarized Th1 immunity, whereas DCIR2‐targeted LcrV induced fewer CD4⁺ T cells secreting IFN‐γ, but higher IL‐4, IL‐5, IL‐10, and IL‐13 production. DCIR‐2 targeting elicited higher anti‐LcrV Ab titers than DEC targeting, which were comparable to a protein vaccine given in alhydrogel adjuvant, but the latter did not induce detectable T‐cell immunity. When DEC‐ and DCIR2‐targeted and F1‐V+ alhydrogel‐vaccinated mice were challenged 6 wk after vaccination with the virulent CO92 Y. pestis, the protection level and Ab titers induced by DCIR2 targeting were similar to those induced by F1‐V protein with alhydrogel vaccination. Therefore, LcrV targeting to DC elicits combined humoral and cellular immunity, and for the first time with this approach, also induces protection in a mouse model for a human pathogen.