Previous studies have demonstrated that oxymatrine may inhibit ventricular remodeling and serves an important role in the treatment of cardiovascular disease. The present study investigated whether oxymatrine treatment protects against the effects of cardiopulmonary resuscitation (CPR) via regulation of the transforming growth factor‑β1 (TGF‑β1)/mothers against decapentaplegic (Smad) signaling pathway. A CPR model was established in Sprague‑Dawley (SD) rats by asphyxiation, and rats were subsequently anaesthetized by intraperitoneal injection of chloral hydrate. SD rats were then administered 25 or 50 mg/kg oxymatrine once a day for 4 weeks. Oxymatrine treatment significantly improved troponin I levels, the ejection fraction, hydroxyproline content and the myocardial performance index in model rats. However, treatment with oxymatrine significantly reduced arterial oxygen tension, arterial lactate levels and oxygen extraction. Treatment with oxymatrine following CPR significantly inhibited the protein expression levels of TGF‑β1, TGF‑β1 receptor type 1 and Smad homolog 3 (Smad3) in model rats. The results of this research indicated that oxymatrine treatment may protect against the effects of CPR via regulation of the TGF‑β1/Smad3 signaling pathway and may be a novel drug for CPR in a clinical setting.