Objective To investigate the mechanisms of protective effects of dexmedetomidine on lungs in patients of sepsis complicated with acute respiratory distress syndrome (ARDS). Methods The adult patients with sepsis complicated with ARDS, the oxygenation index (PaO2/FiO2) was 150-200 mmHg (1 mmHg = 0.133 kPa), acute physiology and chronic health evaluationⅡ (APACHEⅡ) score was 10-20, need mechanical ventilation (MV) treatment > 72 hours, and admitted to intensive care unit (ICU) of the First Affiliated Hospital of Guangxi Medical University from September 2013 to June 2017 were enrolled. According to the random number table method, the patients were divided into three groups (n = 80): no sedation group, propofol group (0.3-4.0 mg·kg-1·h-1) and dexmedetomidine group (0.2-0.7 μg·kg-1·h-1). The three groups were adequately analgesic treated with remifentanil. The sedation target was -1-0 of Richmond agitation-sedation score (RASS). The levels of interlenkin-6 (IL-6) and tumor necrosis factor-α (INF-α) were determined by enzyme linked immunosorbent assay (ELISA) before sedation, and 24, 48, 72 hours after sedation. The expressions of inflammatory signaling proteins in bronchoalveolar lavage fluid (BALF) were determined by Western Blot before sedation and 72 hours after sedation. Results There were no significant changes for inflammatory factors in serum, and inflammatory signaling proteins and anti-apoptotic signaling proteins in alveolar exfoliated cells in no sedation group. The levels of IL-6 and TNF-α in serum and the expressions of Toll-like receptor 4 (TLR4), myeloid differentiation factor 88 (MyD88) and phosphorylated c-Jun N-terminal kinase (p-JNK) in alveolar cells in propofol group and dexmedetomidine group were all significantly reduced after sedation, moreover, it was more significantly in the dexmedetomidine group compared with propofol group [48 hours: TNF-α (ng/L) was 153.76±29.16 vs. 179.82±30.28;72 hours: IL-6 (ng/L) was 272.18±42.76 vs. 304.49±44.93, TNF-α (ng/L) was 102.18±30.25 vs. 140.28±28.92, TLR4 (IA value) was 0.288±0.034 vs. 0.648±0.029, MyD88 (IA value): 0.356±0.030 vs. 0.752±0.044, p-JNK (IA value): 0.256±0.027 vs. 0.303±0.034, all 1 < 0.05]. The expression of p-Akt in alveolar cells in propofol group and dexmedetomidine group was all significant increased after sedation, moreover, it was more significantly in the dexmedetomidine group compared with propofol group (IA value: 1.032±0.030 vs. 0.743±0.028, 1 < 0.05). Conclusion Dexmedetomidine exerts the protective effects on lungs in patients of sepsis complicated with ARDS through the TLR4-MyD88-JNK signaling pathway.