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Cyclin-dependent kinase 4/6 inhibitors (CDK4/6Is), including ribociclib, are used alongside endocrine therapy for hormone receptor-positive (HR+) and human epidermal growth factor receptor 2-negative metastatic breast cancer. Ribociclib-induced colitis is a rare drug reaction with unknown incidence, lack of discovery in clinical trials, and only one other published case. We describe a case of ribociclib-induced colitis and subsequent management. A female with metastatic HR+ breast cancer in her 60s was prescribed letrozole and ribociclib. She developed acute diarrhea, and a surveillance CT demonstrated pan-colitis. After discontinuing ribociclib and completing steroids, the diarrhea resolved. Palbociclib, an alternative CDK4/6I, was initiated as replacement. The patient tolerated palbociclib for up to 5 months at the time of publication without recurrence of colitis. Postmarket drug surveillance is crucial to prevent diagnostic delays. An investigation into CDK4/6-induced colitis, relative risks between agents, and potential risk factors is needed.