Diarylheptanoids, extracted from the Curcuma comosa (CC) rhizome, have been reported to exhibit estrogenic activity. However, oral administration of the extract showed a short half-life. This study aimed to formulate and to investigate the potential of transfersomal gels for the transport of phytoestrogenic diarylheptanoids across the skin into the blood circulation. The transfersomes were developed and optimized for their compositions including sources of phospholipid (egg yolk and soybean), types of edge activators (polysorbate 80, sorbitan oleate 80, and sodium cholate), and concentrations of CC extract (10-60 mg). The optimal formulation was further incorporated into Carbopol® Ultrez 21 gel and evaluated for in vitro release, permeation, and in vivo absorption. The optimal transfersomes containing 10% of polysorbate 80 were selected due to high drug entrapment efficiency and a small diameter. The release kinetic of transfersomal gels followed a zero model. The maximum permeation flux through porcine ear skin was 1.38 ± 0.25 µg/cm2/h for (4E, 6E)-1, 7-diphenylhepta-4, 6-dien-3-ol, and 0.40 ± 0.11 µg/cm2/h for (6E)-1, 7-diphenylhept-6-en-3-ol. Results of the in vivo pharmacokinetics study in rats showed that transfersomal gel provided a maximum concentration of 219.71 ± 4.05 ng/ml and prolonged plasma concentration of diarylheptanoids for over 12 h. There was no significant variation found in the physical characteristics including viscosity, pH, and size after six months of storage at room temperature (30 ± 1 °C) and high temperature (40 ± 1 °C). The obtained data suggested that the developed transfersomal gel of CC extract should be beneficial for improving the delivery of phytoestrogenic diarylheptanoids.