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Epiploic appendagitis is a rare, self-limiting inflammatory condition of the colonic epiploic appendages. It commonly presents with acute focal lower quadrant abdominal pain and may mimic appendicitis, colitis, or diverticulitis. Rapid weight loss has been proposed as a potential predisposing factor, although clinical evidence remains limited. This report describes a case of epiploic appendagitis occurring in temporal association with substantial and relatively rapid weight reduction during treatment with tirzepatide, a dual glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1) receptor agonist. A 45-year-old individual with a history of obesity, prediabetes, hypertension, hypothyroidism, and inflammatory bowel syndrome presented to primary care with right lower quadrant abdominal pain. Initial evaluation attributed symptoms to constipation; however, pain progressed despite management. Computed tomography (CT) of the abdomen and pelvis with contrast was obtained due to concern for appendicitis and demonstrated imaging findings consistent with epiploic appendagitis localized to the cecum. The patient had experienced clinically significant and relatively rapid weight loss during tirzepatide dose escalation prior to presentation. Management was conservative with nonsteroidal anti-inflammatory drugs and supportive care, without surgical intervention. Symptoms resolved completely within two weeks, and tirzepatide therapy was continued without recurrence. Although epiploic appendagitis has not been identified as a safety signal in randomized trials, systematic reviews, or pharmacovigilance analyses of GLP-1/GIP receptor agonists, this case highlights epiploic appendagitis as an important diagnostic consideration in patients presenting with focal abdominal pain during periods of substantial weight loss. Awareness of this uncommon condition may help prevent misdiagnosis and unnecessary interventions as pharmacologic weight loss therapies become more widely used.