Cyclin-dependent kinase (CDK) 4/6 inhibitors given with endocrine therapy are standard of care for the treatment of women with advanced hormone receptor (HR) positive and human epidermal growth factor receptor 2 (HER-2) negative breast cancer. Ribociclib is a CDK 4/6 inhibitor with moderate to solid inhibition of CYP3A4, a member of the cytochrome P450 family oxidase system, which may lead to interactions with medicinal substrates that are metabolized via CYP3A4. Statins are among the most widely prescribed medications worldwide, predominantly metabolized by the CYP3A4 isoenzyme. Rhabdomyolysis is a known rare side effect of statins, commonly triggered by drug interactions. We report a case of a 73-year-old woman with metastatic HR-positive and HER-2 negative breast cancer who developed rhabdomyolysis and acute kidney injury due to interaction between simvastatin and ribociclib with a literature review.