Obesity is a significant risk factor for the development of gallstone disease, and the likelihood of its occurrence increases further during periods of rapid weight loss. This phenomenon is observed both in patients undergoing bariatric surgery and in those receiving pharmacological treatment, including glucagon-like peptide-1 (GLP-1) receptor agonists and dual glucose-dependent insulinotropic polypeptide (GIP)/GLP-1 receptor agonist. Mechanisms promoting gallstone formation include increased cholesterol saturation of bile, impaired gallbladder emptying, and metabolic changes associated with substantial weight loss. Ursodeoxycholic acid reduces cholesterol saturation of bile, decreases intestinal cholesterol absorption and its secretion into bile, and enhances bile flow. These properties support its use in the prevention of cholesterol gallstone formation. The results of randomized clinical trials and meta-analyses indicate that prophylactic administration of ursodeoxycholic acid may reduce the incidence of gallstone disease, particularly in patients undergoing bariatric procedures and during periods of active weight loss. Data on the routine use of ursodeoxycholic acid in patients treated with GLP-1 receptor agonists or dual GIP/GLP-1 receptor agonist are lacking. The decision to initiate prophylaxis should therefore take into account individual risk factors, the rate and extent of weight loss, a history of gallstone disease, and the type of treatment administered. Preventive management should be complemented by appropriate lifestyle and dietary modifications.