Ulcerative colitis (UC) is a long-term inflammatory bowel disease (IBD) associated with significant morbidity. It is marked by inflammation and damage to the colon's mucosal lining. Studies have shown that NLRP3 inflammasome activation, apoptosis, and impaired autophagy are critical in its pathogenesis. Verapamil, a calcium channel blocker, has been found to inhibit NLRP3 inflammasome activation in various preclinical models. However, the potential influence of verapamil on the TXNIP in UC remains unexplored. This study investigates the effects of verapamil on an UC rat model induced chemically by acetic acid. Verapamil effectively inhibited the TXNIP-NLRP3-caspase-1 axis, reducing inflammasome activation and the release of IL-1beta and IL-18. Additionally, verapamil suppressed NFkappaB, the priming step of NLRP3 activation. The drug enhanced autophagic activity, as indicated by increased expression of LC3-II and Beclin-1, along with reduced LC3-I and mTOR expression. Moreover, it demonstrated anti-apoptotic effects mediated by regulating Bax and cleaved caspase-3. These molecular changes contributed to mucosal healing and improved microscopic and macroscopic outcomes in the colitis model. Furthermore, verapamil improved the colon weight-to-length ratio and disease activity scores and mitigated oxidative stress. As verapamil has been safely used in clinics to treat hypertension, our findings suggest it may be a safe therapeutic option for ameliorating inflammation and apoptosis and activating autophagy in UC pathology. Since hypertension demonstrates a strong association with UC, the use of verapamil merits particular attention in hypertensive patients fighting against IBD.