Background: The natural history and prognosis of mesenteric panniculitis (MP) are not well-described. Despite referral for colonoscopy being common for this indication, colonoscopy findings in MP patients have not been reported. Therefore, we aimed to describe upper and lower gastrointestinal (GI) endoscopy findings in patients with mesenteric panniculitis, compared to matched controls, to investigate their clinical outcomes including incidence of malignancy and mortality. Methods: Retrospective case–control study was conducted, and included patients who were diagnosed with mesenteric panniculitis according to Coulier radiologic criteria on abdominal computerized tomography between 1/2005 and 12/2019, and followed to 12/2021. The case group was compared to a matched control group without MP on abdominal CT. Clinical data and the upper and lower endoscopies’ reports were reviewed in both groups. We excluded patients who, beyond diagnosis of MP, were also diagnosed with current malignancy, significant intra-abdominal morbidity or inflammatory bowel disease. Results: The initial set of 376 patients with MP, after exclusion, included 187 patients. A total of 56.1% were male, with a mean age 60 ± 15 years. Of them, 74 (39%) patients underwent follow-up CT scans, which demonstrated, in 66 (89.2%) patients, a stable MP without any aggravation. Colonoscopy was performed in 89 MP patients, and 98/187 controls. No significant difference in the colonoscopies’ findings was found between the two groups. Gastroscopy was performed in 84 MP and 79 controls. No case of gastric cancer was found. No statistically significant difference was found in the rate of gastroscopy findings. By the end of the follow-up period, malignancy was diagnosed in four patients of the MP group. None were colon cancer. The mortality rate in the MP group was 3.2%, without a significant difference compared to the controls. None were MP related. Conclusions: MP identified on abdominal CT is not associated with pathologic endoscopy findings or future diagnosis of colon cancer, and also has no impact on mortality rate. Since repeating abdominal CT did not reveal any disease progression, the necessity of follow-up imaging for MP should be carefully reconsidered.