Smoke-induced acute lung injury (ALI) is a grievous disease with high mortality. Despite advances in medical intervention, no drug has yet been approved by the Food and Drug Administration (FDA) for ALI. In this study, we reported that pretreatment with high-molecular-weight hyaluronan (1600 kDa, HA1600) alleviated pulmonary inflammation and injury in mice exposed to smoke and also upregulated long non-coding RNA (lncRNA) metastasis-associated lung adenocarcinoma transcript 1 (MALAT1), as well as suppressor of cytokine signaling-1 (SOCS-1), in the lung tissues. Next, we overexpressed MALAT1 in the lungs by intratracheal administration of adenovirus cloned with MALAT1 cDNA and found that the survival of mice after smoke exposure was improved. Moreover, pulmonary overexpression of MALAT1 ameliorated smoke-induced ALI in mice and elevated the level of SOCS-1 in the lungs. In conclusion, the results pointed out that HA1600 exerted a protective effect against smoke-induced ALI through increasing the MALAT1 level and the subsequent SOCS-1 expression. Our study provides a potential therapeutic approach to smoke-induced ALI and a novel insight into the mechanism of action of HA1600.