Rosai-Dorfman disease (RDD), also called sinus histiocytes, is a rare disease of enlarged lymph nodes with no known etiology. It mainly involves the cervical lymph nodes. The presentation of RDD with isolated mesenteric lymph node involvement has not been reported previously. Here, we report a case of isolated mesenteric lymph node involvement caused by RDD in a 16-year-old boy. He presented with intermittent right lower quadrant pain, fever, altered bowel habits, and unintended weight loss for the past 2 months. Initial clinical and radiological findings were consistent with lymphoma with ileoileal intussusception. A laparoscopic biopsy of the lymph node was performed. Histopathology and immunochemistry studies of the lymph node confirmed the diagnosis of RDD. The clinical symptoms and lymph nodes resolved spontaneously after 6 months of keen observation, confirmed on a positron emission tomography (PET) scan.