Background <p>Cardiac lipid metabolism is easily affected by the surrounding environment, which is involved in the development of heart disease. Salvianolic acid A (SAA) is a phenolic acid with good therapeutic effects on cardiovascular disease. However, the mechanism of how SAA coordinates the crosstalk of oxidative stress and inflammation to reduce the lipid induced-cardiomyocyte injury has not been reported. This study aimed to explore how SAA alleviates lipotoxicity of cardiomyocytes by regulating the crosstalk of oxidative stress and inflammation.</p> Methods <p>Palmitate (PA)-injured H9c2 model was used to mimic lipotoxic myocardial injury. Cardiomyocyte viability and damage was detected by CCK-8 and LDH assay, respectively. Apoptosis was evaluated by TUNEL staining. Intracellular lipid accumulation was detected by fluorescent lipid probe. Inflammation cytokines (IL-1β, TNF-α and IL-6) and oxidative stress levels (ROS, SOD and MDA) were examined as well. Meanwhile, levels of related proteins involved in Akt/Nrf2/NF-κB axis were determined by western blotting and immunofluorescent staining. Furthermore, Akt inhibitor (MK2206) and si-Nrf2 RNA were used to preliminarily confirm the mechanism of SAA on regulating oxidative stress and inflammation crosstalk.</p> Results <p>SAA memorably alleviated PA-injured H9c2 cardiomyocytes from apoptosis, oxidative stress and inflammation. SAA increased the levels of Akt and GSK-3β phosphorylation and nuclear translocation of Nrf2, while decreased the levels of NF-κB phosphorylation and nuclear translocation. Furthermore, the anti-apoptosis and anti-oxidation effects of SAA were restrained as a result of the MK2206 intervention, while the anti-inflammatory effects partially disappeared due to the silenced Nrf2.</p> Conclusion <p>SAA prevents PA-induced cardiotoxicity by orchestrating oxidative stress and inflammation via Akt/Nrf2/NF-κB axis.</p>