The potential of the administration of Harpagophytum procumbens extract via the topical route has not been studied previously. In the current work, the dermal and transcutaneous delivery of the major pharmacologically active constituents present in H. procumbens tuber extract were determined across porcine ear skin from four vehicles: de-ionised water, 30 % ethanol in water (v/v), PEG 400, 50 : 50 PEG 400 in 30 % EtOH (v/v). Permeation profiles were obtained under infinite conditions and tape stripping was performed at 24 h. The permeation of the compounds varied according to their physicochemical properties as well as the nature of the vehicle. The highest permeation was found from the ethanol/water saturated solutions and the lowest MW harpagide was obtained at significantly higher concentrations in the receptor phase compared to the rest of the compounds, with the permeability coefficient being inversely dependent on dielectric constant of the vehicle. Depth profiling revealed higher penetration of all compounds from ethanol/water; in addition, significantly higher amounts of the pro-inflammatory harpagide were present in the strips and the remaining epidermis compared to other compounds. This suggests that ethanol is not a suitable vehicle as it leads to more harpagide penetration, potentially counteracting the anti-inflammatory activity of the other compounds. The development of new systems for local cutaneous inflammation (e. g., psoriasis, eczema) and subcutaneous inflammation (e. g., arthritis) is supported.