The present research focused on formulating and characterizing an ophthalmic in situ gel incorporating Strychnos potatorum Linn. extract to enhance ocular residence time and achieve sustained drug release. Conventional eye drops often exhibit poor bioavailability due to rapid precorneal clearance; hence, thermosensitive in situ gels capable of liquid-to-gel transition upon ocular administration were developed. A three-level factorial design coupled with response surface methodology (RSM) was employed to optimise formulation variables, using Poloxamer 407 and Hydroxypropyl Methylcellulose (HPMC) as key independent factors. The developed gels were systematically evaluated for pH, viscosity, clarity, and gelling capacity. Among the formulations, F6 demonstrated optimal characteristics, including physiological pH (5.7–6.7), desirable viscosity (3–6 cPs), high clarity, and rapid sol–gel transformation ensuring prolonged ocular retention. In vivo assessments using a selenite-induced cataract model in Wistar rat pups indicated that the optimized formulation provided 59% protection against cataract formation and effectively restored oxidative balance, evidenced by reduced malondialdehyde (MDA) levels alongside increased superoxide dismutase (SOD) and catalase activities. Histopathological observations confirmed preservation of lens structure, while Draize testing in rabbits showed good ocular tolerance without irritation. Overall, the study establishes the Strychnos potatorum–based ophthalmic in situ gel as a safe and promising herbal delivery system for oxidative stress– related ocular disorders, warranting further preclinical and clinical evaluation