Introduction: A major problem in ocular therapeutics is the attainment of optimum drug concentration at the site of action, which is compromised mainly due to precorneal loss resulting in only a small fraction of the drugs being absorbed. The effective dose administered may be altered by increasing the retention time of medication into the eye by using in situ gel forming polymeric systems. Materials and Methods: In the present investigation, an attempt has been made to design, formulate, and evaluate in situ gelling-based ophthalmic drug delivery system dorzolamide hydrochloride to enhance the precorneal retention and to improve the ocular bioavailability. In situ gel formulations are designed using carboxy methyl tamarind, a polysaccharide, was used with other natural polymers such as xanthan gum, gellan gum, and sodium alginate. The in situ gel formulations were characterized for physicochemical characters, namely physical appearance, pH measurement, gelling capacity, drug content estimation, rheological study, effect of sterilization on the viscosity, in vitro diffusion study mucoadhesive strength, sterility testing, preservative efficacy testing, isotonicity testing, and ocular irritation testing. Results and Discussion: The developed formulations exhibited sustained release of drug from formulations over a 9 h period, thus increased residence time of the drug. Effect of sterilization was studied to check the rigors of sterilization on the viscosity of the formulations. In the study, two optimized formulations were selected on the basis of ability to form good gelling with increased viscosity with a slow and prolong in vitro drug release pattern. The formulations were found to be nonirritating with no ocular damage or abnormal clinical signs observed. Conclusion: Therefore, the developed ophthalmic in situ gel by virtue of its prolonged corneal residence time and sustained drug release could be considered a viable alternative to the conventional eye drops formulation in achieving enhanced bioavailability.