Doxorubicin (DOX), is one of the most widely-used chemotherapeutic drugs. Despite its broad therapeutic efficacy, clinical studies have reported that, the major limiting factor of DOX chemotherapy is its significant cardiotoxic effects, which often results in irreversible degenerative cardiomyopathy and heart failure. Lycopene and saffron are powerful antioxidants against free radicals and oxidative attacks.Human trials should be carried out to establish the potential protective effects of lycopene and saffron. Future experiments are required to evaluate the possible protective molecular mechanisms of lycopene and saffron against DOX-induced cardiotoxicity.