AIM: To investigate the effect of dexmedetomidine (Dex) on reducing doxorubicin-induced cardiotoxicity by downregulating RNA-binding motif protein 3 (RBM3) through inhibiting ferroptosis. METHODS: Two-month-old SPF SD rats were randomly divided into control group (Control), adriamycin group (Adr), doxorubicin+ dexmeadriamycin group (Adr+Dex), and adriamycin+dexmedetomidine+ferroptosis agonist group (Adr+Dex+Era). The Adr group was given 2.5 mg/kg of Adr every other day for a total of 6 times; the Adr+Dex group was given Adr every other day and Dex 50 μg/kg every day for a total of 19 times; the Adr+Dex+Era group was given Adr and Dex in the same way, and 10 mg/kg of Era was given every other day for 14 days for a total of 3 times. The control group was given equal volumes of normal saline and DMSO solvent. The rats were anesthetized and sacrificed on day 19, and the ventricles were removed for Sirius to detect fibrosis, immunohistochemistry to detect RBM3 expression, Prussian blue staining to detect iron deposition, Western blotting and PCR to detect RBM3 expression. RESULTS: Compared with the Adr group, the Adr+Dex group significantly inhibited the increase of fibrosis caused by Adr, reduced the upregulation of RBM3 caused by Adr, and improved the iron deposition caused by Adr. The ferroptosis agonist Era reversed the protective effect of Dex again. CONCLUSION: Dex inhibits ferroptosis, downregulates RBM3 expression, and improves adriamycin-induced myocardial toxicity without affecting the anti-tumor effect of Adr.