Background <p>Human epidermal growth factor receptor 2 (HER2)-positive breast cancer is an aggressive subtype. While trastuzumab plus pertuzumab significantly improves outcomes, cardiotoxicity remains a major limitation. Traditional Chinese Medicine (TCM) posits that <i>Platycodon grandiflorus</i> A. DC. (PG) may offer cardioprotection by addressing “Qi deficiency” and “blood stasis”. This study aims to investigate the efficacy and safety of PG granules (PGG) in preventing anti-HER2 therapy-associated cardiotoxicity.</p> Method <p>In this double-blind, randomized, placebo-controlled trial, approximately 120 patients with HER2-positive early breast cancer initiating trastuzumab and pertuzumab will be randomly assigned (1:1) to receive either PGG or placebo granules for 18 weeks (6 cycles of 3 weeks). The primary outcome is left ventricular ejection fraction (LVEF) measured within 3 days after completing anti-HER2 therapy. Secondary outcomes include: (1) incidence of cardiotoxicity (LVEF decline to &lt; 55% or &gt; 10% drop from baseline), (2) changes in left ventricular global longitudinal strain (GLS), (3) levels of B-type natriuretic peptide (BNP) and troponin I (TnI), (4) incidence of trastuzumab plus pertuzumab interruption due to cardiotoxicity, and (5) event-free survival (EFS) and overall survival (OS). Safety will be monitored according to NCI-CTCAE v4.03.</p> Discussion <p>This is the first clinical trial evaluating PG for preventing cardiotoxicity induced by trastuzumab plus pertuzumab in HER2-positive early breast cancer. Results will provide essential pilot data for future larger studies on integrative cardioprotective strategies.</p> Trial registration <p>Chinese Clinical Trial Registry (ChiCTR2200061011).</p>