Aims Cardiac malfunctions developing in result of sepsis are hard to treat so they eventually contribute to the increased mortality. Previous reports indicated for therapeutic potential of exogenous omega-3 polyunsaturated fatty acids (PUFA) in sepsis, but potential benefits of this compound on the malfunctional heart have not been explored yet. In the present study, we investigated whether the constantly elevated levels of endogenous omega-3 PUFA in transgenic fat-1 mice would alleviate the lipopolysaccharide (LPS)-induced cardiac failure and death. Methods and results After both wild type (WT) and transgenic fat-1 mice were challenged with LPS, a Kaplan-Meier curve and echocardiography were performed to evaluate the survival rates and cardiac function. Proteomics analysis, RT-PCR, western blotting, immune-histochemistry, and transmission electron microscopy were further performed to investigate the underlying mechanisms. Results showed that transgenic fat-1 mice exhibited the significantly lower mortality after LPS challenge as compared with their WT counterparts (30% vs. 42.5%, P < 0.05). LPS injection consistently impaired the left ventricular contractile function and caused the cardiac injury in the wild type mice, but not significantly affected the fat-1 mice (P < 0.05). Proteomic analyses, ELISA, and immunohistochemistry further revealed that myocardium of the LPS-challenged fat-1 mice demonstrated the significantly lower levels of pro-inflammatory markers and ROS than WT mice. Meaningfully, the LPS-treated fat-1 mice also demonstrated a significantly higher levels of LC3 II/I and Atg7 expressions than the LPS-treated WT mice (P < 0.05), as well as displayed a selectively increased levels of peroxisome proliferator-activated receptor (PPAR) gamma and sirtuin (Sirt)-1 expression, associated with a parallel decrease in NF kappa B activation. Conclusions The fat-1 mice were protected from the detrimental LPS-induced inflammation and oxidative stress, and exhibited enhancement of the autophagic flux activities, associating with the increased Sirt-1 and PPAR gamma signals.