Cisplatin resistance is a major obstacle in the treatment of NSCLC, and its mechanism has not been fully elucidated. The objectives of the study were to determine the role of miR-378 in the sensitivity of lung adenocarcinoma cells to cisplatin (cDDP) and its working mechanism. With TargetScan and luciferase assay, miR-378 was found to directly target sCLU. miR-378 and sCLU were regulated in A549/cDDP and Anip973/cDDP cells to investigate the effect of miR-378 on the sensitivity and apoptotic effects of cDDP. The effect of miR-378 upregulation on tumor growth was analyzed in a nude mouse xenograft model. The correlation between miR-378 and chemoresistance was tested in patient samples. We found that upregulation of miR-378 in A549/cDDP and Anip973/cDDP cells significantly down-regulated sCLU expression, and sensitized these cells to cDDP. miR-378 overexpression inhibited tumor growth and sCLU expression in a xenograft animal model. Analysis of human lung adenocarcinoma tissues revealed that the cDDP sensitive group expressed higher levels of miR-378 and lower levels of sCLU. miR-378 and sCLU were negatively correlated. To conclude, we identified sCLU as a novel miR-378 target, and we showed that targeting sCLU via miR-378 may help disable the chemoresistance against cisplatin in lung adenocarcinoma cells.