HER2-positive breast cancer represents a biologically aggressive subtype associate with poor prognosis, despite advances in targeted therapies. Cyclin-dependent kinase 4/6 inhibitors (CDK4/6i), initially approved for hormone-receptor-positive, HER2-negative disease, are now being explored in HER2-positive settings due to their mechanistic synergy with the HER2 signaling pathway. This review synthesizes evolving clinical evidence from trials and highlights further research into biomarker discovery. CDK4/6i may redefine treatment paradigms in HER2-positive breast cancer, offering a potential, non-chemotherapy option with durable benefit in select patient populations.