Immune checkpoint inhibitors (ICPI) are a class of chemotherapy agents that have emerged as a front-line treatment option for multiple cancers. Nivolumab is an ICPI agent commonly used to treat metastatic melanoma. Although promising, the adverse reaction of this class is broad and per reports, the incidence of colitis is <6%. We present the case of a 71-year-old male with a history of metastatic melanoma who was being treated with nivolumab. The patient was two weeks into his treatment regimen when he began complaining of multiple loose, bloody stools. Because of these symptoms, his nivolumab was discontinued. However, despite discontinuation, his symptoms persisted and the patient underwent a colonoscopy. He was found to have diffuse inflammation of the colon and was diagnosed with nivolumab-induced colitis. Subsequently, the patient underwent multiple treatments, including high-dose steroids, infliximab, and vedolizumab (Entyvio), with no resolution of symptoms. After several months of failed treatment, the patient was readmitted to the hospital for refractory colitis. He was started on high-dose steroids and underwent a repeat colonoscopy, which again showed diffuse colitis. Because of the previously failed treatment options, mycophenolate, an immunosuppressant, was initiated in combination with his steroids. After three days of high-dose steroids and mycophenolate, the patient's symptoms resolved, with no subsequent apparent symptoms of colitis. We present a case of nivolumab-induced colitis, refractory to multiple immunosuppressive medications, which was successfully treated with mycophenolate and high-dose steroids.