Introduction Bevacizumab, a humanized monoclonal antibody targeting Vascular Endothelial Growth Factor (VEGF), is a therapeutic cornerstone for recurrent glioblastoma, yet its inhibition of angiogenesis fundamentally disrupts vascular homeostasis. While gastrointestinal perforation is a documented risk, severe ischemic colitis presenting as Non-Occlusive Mesenteric Ischemia (NOMI) associated with systemic thrombosis is a rare, life-threatening complication driven by endothelial dysfunction, vascular rarefaction, and potent splanchnic vasoconstriction via the nitric oxide pathway. We present a highly educational case highlighting the diagnostic challenges and the feasibility of conservative management in this complex vascular scenario. Case Presentation We report the case of a 57-year-old male with IDH-wildtype glioblastoma. Following tumor recurrence, the therapeutic regimen was intensified to high-dose Bevacizumab (800 mg) combined with Lomustine. Within weeks of dose escalation, the patient presented with acute, severe diffuse abdominal pain, hematochezia, and laboratory evidence of marked inflammation and tissue hypoperfusion (elevated lactate). Contrast-enhanced Computed Tomography (CT) revealed a complex vascular picture characterized by distal pulmonary embolism and diffuse, circumferential colonic wall thickening with a "target sign" and pericolic fat stranding; crucially, the celiac and mesenteric arteries were patent, excluding proximal embolic occlusion and supporting a diagnosis of drug-induced microangiopathy. Colonoscopy confirmed severe ischemic colitis extending from the sigmoid to the cecum, characterized by mucosal edema, cyanosis, friability, and longitudinal ulcerations, while biopsies revealed neutrophilic cryptitis, regenerative changes, and fibrin thrombi. Management and Outcome Bevacizumab was permanently discontinued. The case posed a significant therapeutic dilemma involving the balance between the risk of exacerbating active gastrointestinal bleeding and the necessity of treating the pulmonary embolism. A multidisciplinary team opted for a conservative, organ-sparing strategy given the absence of transmural necrosis signs. Anticoagulation with therapeutic enoxaparin was initiated under strict surveillance, alongside oral mesalazine to mitigate ischemic-induced inflammation and short-term anaerobic coverage. The patient’s clinical status improved rapidly, rectorrhagia ceased within 48 hours, and he was discharged without surgical intervention. Conclusion This case highlights that high-dose anti-VEGF therapy can precipitate a "perfect storm" of systemic thrombosis and intestinal ischemia. Clinicians must maintain a high index of suspicion for NOMI in patients presenting with abdominal pain even in the absence of macrovascular occlusion on CT, as early conservative management with careful anticoagulation is a viable therapeutic pathway requiring close multidisciplinary collaboration.