<p>Glaucoma is a leading cause of irreversible blindness worldwide, characterized by optic nerve damage that is often associated with elevated intraocular pressure. Topical antiglaucoma medications, such as prostaglandin analogues, β-blockers, carbonic anhydrase inhibitors, α-adrenergic agonists, and Rho-kinase inhibitors, represent the mainstay of treatment; however, long-term therapy with these drugs is invariably associated with ADRs, including conjunctival hyperemia, ocular surface inflammation, Meibomian gland dysfunction, and tear film instability. These generally result from drug-induced structural and physiological changes in the conjunctiva, cornea, and tear film. In recent years, compelling evidence has emerged that supplementation with omega-3 fatty acids and hyaluronic acid can prevent and alleviate these ADRs. Omega-3 fatty acids suppress ocular surface inflammation, enhance tear film stability, and improve meibomian gland function, while HA enhances corneal healing, ocular surface lubrication, and epithelial regeneration. In addition, ocular barriers in the eye often impede the poor bioavailability of conventional topical medications, necessitating the development of NDDS. Nanoparticles, nanoemulsions, in-situ gels, and ocular inserts exhibit improved corneal permeability, prolonged retention time, and sustained drug release, thereby offering superior therapeutic outcomes with less local irritation. Combining omega-3 fatty acids and HA with NDDS may thus represent a new strategy to improve ocular drug delivery while minimizing ADRs associated with chronic antiglaucoma medications. This review highlights the mechanism underlying these side effects and discusses new opportunities to improve drug safety and compliance in long-term glaucoma management.</p> Graphical abstract <p>ADRs associated with antiglaucoma medication and their mitigation</p> <p></p>