A high-fat diet has been shown to exacerbate the cardiotoxicity associated with the chemotherapy drug doxorubicin (DOX); however, it is unknown whether switching from a high-fat diet to a low-fat diet can attenuate the intensified DOX cardiotoxicity. The purpose of this study was to investigate the effects of a low-fat diet on DOX-induced cardiotoxicity in rats previously fed a high-fat diet. Male rats were randomly assigned to consume a Western diet or a low-fat diet for 6 weeks. Western diet-fed rats were then further randomized to switch to the low-fat diet (WD-LF) or continue with the Western diet (WD). One week later, WD-LF and WD received 1 mg/kg DOX per day for 10 consecutive days and continued with their diets (WD-LF + DOX, WD + DOX). LF was further randomized to receive 1 mg/kg DOX per day for 10 consecutive days (LF + DOX) or saline injections as a control (LF + SAL). Four weeks following the first injection, cardiac function was analyzed, and left ventricles were analyzed for cardiotoxicity indices. When compared to LF + SAL and LF + DOX, WD + DOX exhibited an enhanced cardiotoxicity as evidenced by reduced septal wall thickness, fractional shortening, and sarco-endoplasmic reticulum Ca2+ ATPase expression as well as increased left ventricular cavity dimensions, lipid peroxidation, and β-myosin heavy-chain expression. This exacerbated cardiotoxicity was not observed in WD-LF + DOX. Switching to a low-fat diet 1 week prior to, during, and following DOX treatment attenuated the exacerbated cardiotoxicity observed in the previously Western diet-fed rats.