Dendritic cells (DCs) are the major specialized antigen-presenting cells for the development of optimal T-cell immunity. DCs can be used as pharmacological targets to monitor novel biological modifiers for the cure of harmful immune responses, such as transplantation rejection. Dryopteris crassirhizoma Nakai (Aspiadaceae) is used for traditional herbal medicine in the region of East Asia. The root of this fern plant has been listed for treating inflammatory diseases. Dryocrassin is the tetrameric phlorophenone component derived from Dryopteris. Here we tested the immunomodulatory potential of dryocrassin on lipopolysaccharide (LPS)-stimulated activation of mouse bone marrow-derived DCs in vitro and in skin allograft transplantation in vivo. Results demonstrated that dryocrassin reduced the emission of tumor necrosis factor-α, interleukin-6, and interleukin-12p70 by LPS-stimulated DCs. The expression of LPS-induced major histocompatibility complex class II, CD40, and CD86 on DCs was also blocked by dryocrassin. Moreover, LPS-stimulated DC-elicited allogeneic T-cell proliferation was alleviated by dryocrassin. In addition, dryocrassin inhibited LPS-induced activation of IκB kinase, JNK/p38 mitogen-activated protein kinase, and the translocation of NF-κB. Treatment with dryocrassin noticeably diminished 2,4-dinitro-1-fluorobenzene-reduced delayed-type hypersensitivity and extended skin allograft survival. Dryocrassin may be one of the potent immunosuppressive agents for transplant rejection via the destruction of DC maturation and function.