Background: Phonix dactylifera have been bio-applied for management of diseases. Exploring new applications for date seed by-products can benefit the date producing countries. Doxorubicin (DOX) causes several adverse effects including cardiotoxicity Aim: This study aims to investigate the impact of P. dactylifera seeds extract (PDSE) on cardiotoxicity. Methods: Thirty two male rats were equally divided into: Gp1 was the control; Gp2 was i.p. injected with PDSE (300 mg/kg), Gp3 was i.p injected with DOX (4 mg/kg). Gp4 was injected with DOX as in Gp3, and then administered with PDSE as in Gp2. Biochemical and molecular investigations were evaluated. Results: Treatment with PDSE led to improvement in the cardiotoxicity induced by DOX in male rats that evidenced by significant improvement in the biochemical parameters including cardiac functions, oxidative stress biomarkers, and gene expression of TGF-β/Smad-7 genes in the heart tissues. Conclusion: Phonix dactylifera seeds extract showed potent ameliorative impact against the cardiotoxicity adverse effect by improving cardiac function biomarkers, oxidative stress, and involved TGF-β/Smad-7 pathway.