The purpose of this study was to create suppositories with hydromethanolic extract of Cissus quadrangularis Linn. as a potential treatment for Hemorrhoids. Rapid absorption and high bioavailability are encouraged by the rectal route of drug delivery, which results in an early commencement of action. In-situ gelling suppositories were developed to address issues with first-pass metabolism, medication leakage, and patient discomfort. These suppositories were improved using the Box-Behnken design method with Design-Expert 13 software. The responses assessed included hardness, disintegration time, gelation temperature, and percentage of drug release. Combinations of PEG 600 (30%–50%), PEG 4000 (40%–60%), and Poloxamer 407 (5%–20%) were entered as factors. Tests for physical properties, weight fluctuation, and medication content were all passed by the improved formulation. These formulations displayed a melting point of around 36 ± 0.25 ℃, a pH between 6 and 7, a hardness of about 1.9 ± 0.06 kg/cm2, a disintegration time of about 13 ± 0.47 minutes, a liquefaction time of about 10 ± 0.54 minutes, and an in-vitro drug release of 97.77 ± 0.47%. The extract also showed the abundance of bioflavonoids and other flavonoids in it as it was subjected for HPTLC analysis