The purpose of this study was examined the feasibility of using phytantriol-based cubic and hexagonal liquid crystal preparation for the percutaneous administration of trans-cinnamaldehyde (TCA). TCA-loaded lyotropic liquid crystal formulations were prepared and characterized, their skin permeability in vitro and in vivo was evaluated. Preliminary pharmacodynamics were also investigated in adjuvant arthritics (AA) rats. The formulations were identified respectively as cubic and hexagonal structure. The in vitro permeability study exhibited that both cubic and hexagonal liquid crystal improved the cumulative permeation quantity and permeation rates of TCA compared with home-made gel. The results of an in vivo transdermal permeability experiment showed that the area under the curve [AUC(0–∞)] of the hexagonal and cubic liquid crystal was 1.62 and 1.53 times higher than that of the gel group, respectively. Preliminary pharmacodynamics studies indicated that the group of high-dose TCA-loaded (200 mg·kg−1) hexagonal liquid crystal was shown to inhibit the paw swelling of AA rats, improve synovial hyperplasia and inflammatory cell infiltration, and down-regulate the levels of serum interleukin (IL)-1β and tumor necrosis factor (TNF)-α. Furthermore, there was no significant difference in the anti-inflammatory effects of TCA-loaded hexagonal liquid crystal and the commercially available product Voltaren® emulgel®. Thus, hexagonal liquid crystal was considered as an effective delivery system for TCA.