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Glaucoma and other chronic optic neuropathies are the leading causes of blindness worldwide. These diseases are characterized by damage to the optic nerve at the base of the retina, and most medications targeting optic neuropathies are administered as eye drops. However, since corneal penetration efficiencies are typically <5% for such dosage forms, not only are these formulations ineffective, but the dosage of drug is much higher than required, which incurs higher costs. There is a clear, unmet need for novel transcorneal drug delivery vehicles that achieve higher drug penetration at significantly lower dosages. To this end, we have developed a stimulus-responsive, in situ forming, nanoparticle-laden hydrogel for spatiotemporal and dosage-controlled release of poorly bioavailable drugs into the aqueous humor of the eye. The hydrogel is formulated as a composite of hyaluronic acid (HA) and methylcellulose (MC). Both polymers are biocompatible, highly mucoadhesive and approved by the FDA as GRAS. The amphiphilic nanoparticles are composed of poly(ethylene oxide) (PEO) and poly(lactic acid) (PLA). Experimental design aided the identification of hydrogel composition and nanoparticle content in the formulation for stimulus-responsive switching between thixotropy and temperature-dependent rheopexy. The liquid formulation has a sol-gel transition temperature of 32°C, which is the temperature of the ocular surface, and its gelation characteristics permit the formulation to form a thin, uniform coating over the cornea through blinking of the eyelid. These properties facilitate application of the medication as an eye drop immediately prior to the patient’s bedtime, and also permit easy and scalable manufacturing, which greatly simplifies the path towards development of a regulated industrial-scale manufacturing process. We subsequently tested the efficacy of our formulation in whole-eye experiments using porcine eyeballs by loading the nanoparticles with cannabigerolic acid (CBGA), a molecule that is a close mimic of an approved glaucoma medication. Our formulation exhibits over a 300% increase in transcorneal penetration over control formulations. Our work paves the way for the introduction of novel products targeting ocular diseases to the market.