INTRODUCTION: Cardiovascular diseases, which are non-communicable diseases, are among the leading causes of death worldwide. OBJECTIVE: In this study, we aimed to investigate the efficacy of Lepidium sativum extract, which has antioxidant properties, in preventing cardiac damage in rats with cardiac damage induced by total circulatory arrest, using biochemical and histopathological methods. METHODS: Twenty-four adult male Wistar albino rats weighing 200-250g were used in our study. These rats were randomly divided into four groups. Group 1 (Control, n = 6), Group 2 (Ischaemia (TCA), n = 6), Group 3 (Treatment 1, Ischaemia + Lepidium sativum, n = 6), Group 4 (Treatment 2, Lepidium sativum, n = 6). TOS, TOS, NRF-2, TNF-α, MDA, and HIF-1α parameters were measured in blood plasma and heart tissue using the ELISA kit method. In addition, baseline chemical parameters were examined in plasma. Histopathological examination of heart tissue was performed. RESULTS: There were statistically significant differences between groups in terms of plasma MDA (p < 0.001), HIF-1α (p < 0.001), NRF-2 (p < 0.001), TAS (p < 0.001), TOS (p < 0.05), and TNF-α (p < 0.05) levels; in heart tissue, MDA (p < 0.05), HIF-1α (p < 0.05), NRF-2 (p < 0.05), TAS (p < 0.001), TOS (p < 0.05), and OSI (p < 0.05) parameters were found to be significant. TAS levels were highest in the LS group (p < 0.001), while TOS levels were highest in the Ischaemia group (p < 0.05). CONCLUSION: Lepidium sativum significantly improved cardiac damage in rats with TCA-induced cardiac damage by reducing MDA, HIF-1α, TNF-α, and TOS levels. In addition, histopathological examination revealed that cardiac myocytes had a more regular structure in the group administered the extract. Furthermore, we believe that this study provides valuable data in the field of cardiovascular molecular mechanisms.