Background: 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. Aim of the work: the aim of this study was to investigate and compare the protective effects of tomato Lycopene (LYC) and saffron against DOX induced cardiotoxicity in adult male rats. Material and methods: the study was conducted on 48 adult male albino rats, divided into six groups; group I served as (Control group), group II (Lycopene treated group), group III (Saffron treated group), group IV (Doxorubicin treated group), groupV (Doxorubicin and Lycopene treated group), groupVI (Doxorubicin and saffron treated group). At the end of experiment, all rats were sacrificed and their blood and heart tissues were subjected to biochemical analysis, while the remaining heart tissues were stained for histopathological study. Results: Doxorubicin co-administration with either tomato LYC or saffron showed significant improvements of all studied parameters with the superiority of LYC as regards cardiac enzyme parameters and cardiac troponin. Recommendations: 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