Radiation-induced heart damage (RIHD) is now considered to be one of the causes of mortality in cancer patients undergoing radiotherapy. Cardiac function impairments are clinical manifestations of RIHD. L-carnitine shows protective effects against irradiation and heart disease. This study was aimed to investigate the cardioprotective effects and potential molecular mechanisms of L-carnitine against RIHD. Mouse hearts were exposed to γ-radiation to induce RIHD. L-carnitine at doses of 100 mg/Kg and 200 mg/Kg was used to treat animals intraperitoneally. Additionally, a specific inhibitor of p38 MAPK was used to treat animals by intraperitoneal injections. Cardiac systolic/diastolic functions were determined using invasive hemodynamic methods; myocyte apoptosis was assessed using the TUNEL assay; intracellular reactive oxygen species production was measured using DHE staining; and western blotting was used to evaluate the phosphorylation of p38MAPK, phosphorylation of Nrf2, and expression levels of HO1, NQO1, caspase3 and bax. L-carnitine treatments inhibited irradiation induced cardiac function impairments. Radiation exposure induced myocyte apoptosis and reactive oxygen species production, which were attenuated by L-carnitine treatments. However, administration of a p38 MAPK inhibitor (SB203580) dramatically impaired L-carnitine's effect on attenuating apoptosis, reactive oxygen species accumulation and cardiac functions in irradiated hearts. Our study showed that L-carnitine administration activated p38MAPK/Nrf2 signalling, initiating the expression of HO1 and NQO1, which have anti-apoptotic and anti-oxidative effects, respectively. In conclusion, L-carnitine attenuates cardiac function loss by inhibiting reactive oxygen species production and apoptosis in hearts exposed to radiation. The cardioprotective effects of L-carnitine were mediated by p38MAPK/Nrf2 signalling.