The objective of the present study was to optimize a novel invasomal gel (inva-gel) formulation enriched with terpene for upgrading the therapeutic action of anti-depressant mirtazapine on atopic dermatitis as an off-label use. Various factors were studied by I-optimal design to propose an optimized invasome with desirable characteristics. Its incorporation into different hydrogel bases was targeted to suggest a desirable inva-gel formulation, inspect its ex-vivo performance, and conduct in-vivo pre- and post-sacrifice assessments on atopic dermatitis-induced rats. Results revealed positive ethanol action on increasing entrapment efficiency (up to 77.88%) and decreasing size of invasomal vesicles (from 390.30 nm to 190.60 nm). Increased terpene amounts provided more space for mirtazapine incorporation with enhanced solubility and encapsulation inside invasomes. Terpene's molecular weight and lipophilicity significantly affected physicochemical characteristics of invasomes. More cross-linkages would occur by raising gel:liquid invasome ratio (from 0.5:1 to 2.5:1) and using carbopol other than hydroxylpropyl methyl cellulose (HPMC), therefore increasing rheological properties of inva-gels. Synergistic effects of phospholipid, ethanol, limonene, and carbopol to enhance mirtazapine permeation through skin were observed. Throughout the pre-sacrifice assessments, optimized inva-gel demonstrated a significant decrease in dermatitis severity score (from 8.33 to 3.00) and scratching behavior (from 184.32 s to 37.42 s) in disease-induced rats, hence showing favorable skin profile. Concerning the post-sacrifice assessments, optimized inva-gel significantly alleviated inflammation and pruritus symptoms by minimizing epidermal thickening (from 92.32 μm to 50.17 μm), down-regulating various inflammatory mediators, and decreasing infiltration of inflammatory mast cells. Besides, the ear swelling and spleen index values were markedly decreased (from 77.37 mg to 22.76 mg and from 0.56% to 0.35%, respectively). In conclusion, novel anti-depressant mirtazapine-embedded inva-gel displayed successful transdermal drug permeation offering valuable merits in atopic dermatitis management.