<p>Dry eye disease is a troublesome multifactorial ocular condition, affecting 5–50% of the population. Rebamipide is a mucin secretagogue with anti-inflammatory properties used for dry eye management, however, its efficacy is limited due to its poor aqueous solubility and low tissue permeation. This study aimed to formulate and optimize rebamipide-loaded cubosomes incorporated into a carboxymethyl cellulose gel to achieve a dual action of sustained drug release and enhanced corneal penetration. The proposed cubosomes were prepared via hot melt emulsification technique and optimized applying a 3³ Box-Behnken design. The optimum cubosomes (particle size 173.6±10.89 nm, polydispersity index 0.349±0.04, zeta potential − 29.3±1.2 mV, and drug release 65.89±0.45% at 8 h) exhibited cubic morphology and physical stability for 90 days. Moreover, the rebamipide-loaded cubogel had a uniform spreadability with a shear-thinning, pseudoplastic rheological behavior, and an acceptable pH value for ocular use. Additionally, as per cell culture studies, the cubogel exhibited high safety profile (cell viability &gt; 90%) and potent anti-inflammatory effect. Confocal scanning laser microscopy demonstrated a 2.64-fold increase in corneal tissue permeation of the rebamipide cubogel, as compared to the drug suspension. In-vivo pharmacodynamic study was performed and concluded with the added efficacy of incorporating rebamipide into cubogel form over drug suspension (16-fold rise in nitric oxide inhibitory action). Collectively, the dual-function rebamipide cubogel offers a safe and efficacious platform for dry eye management, integrating prolonged retention with synergistic mucin-stimulating and lubricating effects.</p> Graphical abstract <p></p>