Appropriate modulation of immunity is beneficial in antimicrobial therapy and vaccine development. Host defense peptides (HDPs) constitute critically important components of innate immunity with both antimicrobial and immune regulatory activities. We previously showed that a chicken HDP, namely fowlicidin-1(6-26), has potent antibacterial activities in vitro and in vivo. Here we further revealed that fowl-1(6-26) possesses strong immunomodulatory properties. The peptide is chemotactic specifically to neutrophils, but not monocytes or lymphocytes, after injected into the mouse peritoneum. Fowl-1(6-26) also has the capacity to activate macrophages by inducing the expression of inflammatory mediators including IL-1β, CCL2, and CCL3. However, unlike bacterial lipopolysaccharide that triggers massive production of inflammatory cytokines and chemokines, fowl-1(6-26) only marginally increased their expression in mouse RAW264.7 macrophages. Additionally, fowl-1(6-26) enhanced the surface expression of MHC II and CD86 on RAW264.7 cells, suggesting that it may facilitate development of adaptive immune response. Indeed, co-immunization of mice with chicken ovalbumin (OVA) and fowl-1(6-26) augmented both OVA-specific IgG1 and IgG2a titers, relative to OVA alone. We further showed that fowl-1(6-26) is capable of preventing a methicillin-resistant Staphylococcus aureus (MRSA) infection due to its enhancement of host defense. All mice survived from an otherwise lethal infection when the peptide was administered 1-2 days prior to MRSA infection, and 50% mice were protected if receiving the peptide 4 days before infection. Taken together, with a strong capacity to stimulate innate and adaptive immunity, fowl-1(6-26) may have potential to be developed as a novel antimicrobial and a vaccine adjuvant.