The purpose of the present study was to explore the influence of a certain natural essential oil, namely eucalyptus oil, as an anti-inflammatory agent in addition to its prospective role in enhancing the action of meloxicam in reducing inflammation. As far as we know, this has been the first integration of meloxicam and eucalyptus essential oil into a nanoemulgel formulation intended for topical use. Primarily, eucalyptus oil was utilized in developing a nanoemulsion formulation incorporating meloxicam. A 22 factorial design was constructed using two independent variables (oil concentration and surfactant concentration) with two responses (particle size and % of in vitro release). One optimized formula was selected depending on the desirability function and subjected to a stability study. The optimized nanoemulsion was mixed with HPMC as a gelling agent to produce a meloxicam-loaded nanoemulgel, which was examined for its properties, stability, in vitro release and ex vivo permeation. Eventually, the anti-inflammatory activity was evaluated and compared with a placebo and corresponding gel formulation. The developed nanoemulgel revealed acceptable physical characteristics to be applied topically. Studying of the in vitro release was conducted successfully for 6 h. The ex vivo permeation from the nanoemulgel formulations was prompted, showing an appropriate value of the steady-state transdermal flux (SSTF). As a final point, the anti- inflammatory activity of the developed nanoemulgel revealed a valued anti-inflammatory influence. Additionally, the concurrence of eucalyptus essential oil and meloxicam was assured, and their potential in combating and lowering inflammation was support