Background and Aims Apolipoprotein A‐1 (ApoA‐1), the major apolipoprotein of high‐density lipoprotein, plays anti‐atherogenic role in cardiovascular diseases and exerts anti‐inflammation effect in various inflammatory and infectious diseases. However, the role and mechanism of ApoA‐1 in hepatic ischaemia–reperfusion (I/R) injury is unknown. Methods In this study, we measured ApoA‐1 expression in human liver grafts after transplantation. Mice partial hepatic I/R injury model was made in ApoA‐1 knockout mice, ApoA‐1 mimetic peptide D‐4F treatment mice and corresponding control mice to examine the effect of ApoA‐1 on liver damage, inflammation response and cell death. Primary hepatocytes and macrophages were isolated for in vitro study. Results The results showed that ApoA‐1 expression was down‐regulated in human liver grafts after transplantation and mice livers subjected to hepatic I/R injury. ApoA‐1 deficiency aggravated liver damage and inflammation response induced by hepatic I/R injury. Interestingly, we found that ApoA‐1 deficiency increased pyroptosis instead of apoptosis during acute phase of hepatic I/R injury, which mainly occurred in macrophages rather than hepatocytes. The inhibition of pyroptosis compensated for the adverse impact of ApoA‐1 deficiency. Furthermore, the up‐regulated pyroptosis process was testified to be mediated by ApoA‐1 through TLR4–NF‐κB pathway and TLR4 inhibition significantly improved hepatic I/R injury. In addition, we confirmed that D‐4F ameliorated hepatic I/R injury. Conclusions Our study has identified the protective role of ApoA‐1 in hepatic I/R injury through inhibiting pyroptosis in macrophages via TLR4–NF‐κB pathway. The effect of ApoA‐1 may provide a novel therapeutic approach for hepatic I/R injury.