Eye inflammation is considered one of the most common co-morbidities associated with ocular disorders and surgeries. Conventional management of this condition with non-steroidal anti-inflammatory drugs as eye drops is associated with low corneal bioavailability and ocular irritancy. In the current study, we first investigated the capacity of different solvent systems to enhance the solubility of Meloxicam (MLX). Then, we prepared chitosan nanoparticles loaded with meloxicam (MLX-CS-NPs) through electrostatic interaction between the cationic chitosan and the anionic MLX using either 100% v/v polyethylene glycol 400 or 0.25% w/v tripolyphosphate solution as solvents based on the MLX solubility data. In further studies, MLX-CS-NPs were characterized in vitro and assessed for their ex vivo corneal and scleral permeability. The morphology, average particle size (195–597 nm), zeta potential (25–54 mV), and percent entrapment efficiencies (70–96%) of the prepared MLX-CS-NPs were evaluated. The in vitro release study of MLX from the selected MLX-CS-NPs showed a sustained drug release for 72 h with accepted flux and permeation through the cornea and sclera of rabbits. In the in vivo studies, MLX-CS-NPs eye drop dispersion showed enhanced anti-inflammatory activity and no ocular irritancy compared to MLX-eye drop solution. Our findings suggest the potential for using chitosan nanotechnology for ocular delivery of MLX with high contact time and activity.