Purpose <p>Mesalamine, a BCS Class IV drug approved for ulcerative colitis, possesses poor solubility of 1.41&#xa0;mg/mL and poor bioavailability of 28%. Oxidative stress is a major contributor to colitis and ascorbic acid has been studied to reduce oxidative stress. The presented study focused on formulation of suppository containing Mesalamine drug-drug cocrystals with enhanced solubility for ulcerative colitis.</p> Methods <p>Ascorbic acid was selected as coformer and mesalamine cocrystals were synthesized in 3 ratios of 1:1, 1:2 and 2:1 using the sonication-induced solvent evaporation technique and evaluated for melting point, Differential scanning calorimetry, Xray diffraction studies, Infrared and Raman spectroscopy, NMR spectroscopy, saturation solubility, dissolution, morphology studies, phase transformation studies and drug content. The cocrystals were transformed into glycerogelatin suppositories which were evaluated for several parameters. The drug release of cocrystal containing suppositories was compared with marketed formulation Mesacol^® 250&#xa0;mg.</p> Results <p>The cocrystal in 1:2 ratio was found to exhibit 7 fold increase in solubility which complied with molecular modelling solubility interpretation. FTIR studies and Raman spectral studies confirmed cocrystallization by hydrogen bond formation. The suppositories exhibited physical parameters within permissible limits. The cocrystal containing suppository was found to show a release of 74.4 ± 0.52% at 60&#xa0;min. This drug release was found to be higher than Mesacol ^® 250&#xa0;mg and drug containing suppository which exhibited percent release of 59.3 ± 0.17% and 41.93 ± 0.39% respectively. Mesalamine-ascorbic acid drug-drug cocrystals provide benefits of solubility enhancement and a coadministrative approach in ulcerative colitis.</p> Conclusion <p>The study yielded suppository containing novel Mesalamine cocrystal with superior performance.</p>