Sirtuin6 (SIRT6) continues to be shown to engage in a variety of physiological processes and illnesses, while its role in acute respiratory system distress syndrome (ARDS) remains unclear. Therefore, this research centered on the function and underlying mechanism of SIRT6 in ARDS for the exact purpose of identifying potential therapeutic targets. Within this study, we discovered that SIRT6 was considerably decreased in lipopolysaccharide (LPS)-caused A549 cells along with a murine model. In vitro overexpression of SIRT6 restored the expression of tight junction proteins (ZO-1 and occludin) and alleviated cell apoptosis and inflammation, while knockdown of SIRT6 irritated losing tight junction proteins (ZO-1 and occludin) and promoted cell apoptosis and inflammation in LPS-caused A549 cells. In addition, the overexpression of SIRT6 enhanced autophagy and inhibited the ERK1/2 path, as the knockdown of SIRT6 inhibited autophagy and activated the ERK1/2 path. The autophagy activator rapamycin and also the ERK1/2 inhibitor PD98059 saved the results of SIRT6 knockdown on tight junction proteins, apoptosis, and inflammation. Mechanistically, SIRT6 deacetylated histone 3 at Lys9 to negatively regulate the ERK1/2 path. In vivo, the SIRT6-specific inhibitor OSS_128167 also considerably faster LPS-caused lack of tight junction proteins, lung inflammation, and apoptosis. Meanwhile, the SIRT6-specific inhibitor OSS_128167 also activated the ERK1/2 path and inhibited lung autophagy. These results recommended that SIRT6 could improve losing tight junction proteins, inflammation, and apoptosis in LPS-caused ARDS by inhibiting the ERK1/ 2 path and enhancing autophagy, indicating that SIRT6 plays a advantageous role in ARDS and may well be a potential therapeutic target for ARDS.