Small cell lung cancer (SCLC) is the most aggressive lung-cancer subtype and so far, no favorable therapeutic strategy has been established for chemo-resistant SCLC. Cisplatin is one of the most important components among all standard poly-chemotherapeutic regimens for SCLC; therefore, this study focused on revealing Cisplatin-resistance mechanism(s) in this disease. Cisplatin-resistant SCLC cells were generated in the NCI-H69 xenograft model in nude mice by continuous intravenous administration of Cisplatin; Cisplatin resistance of the tumor cells was confirmed by in vitro and in vivo tests, and the gene expression profile of the resistant cells was determined using microarray analysis. A significantly higher expression of tribbles pseudokinase 2 (TRIB2) mRNA in the Cisplatin-resistant cells was found compared to parental H69 cells. Further, the Cisplatin-resistance level was decreased when TRIB2 expression was knocked down. The mRNA and protein levels of CCAAT/enhancer binding protein alpha (CEBPA), known to be a transcription factor regulating cell differentiation and a target for degradation by TRIB2, as well as selected cancer stem cell makers in the Cisplatin-resistant cells, were measured. We found that CEBPA protein levels could be upregulated by knocking down the overexpressed TRIB2, which also reversed the Cisplatin-resistance of these cells; further, the Cisplatin-resistant SCLC cells demonstrated certain cancer stem cell-like properties. Similar patterns were also observed in limited human tumor specimens of chemo-resistant SCLC patients: namely, overexpressed TRIB2 and undetected CEBPA proteins. Our study revealed a possible molecular mechanism for Cisplatin-resistant SCLC involving induced TRIB2 overexpression and downregulation of CEBPA protein. We propose that this mechanism is a potential therapeutic target to circumvent chemo-resistance in SCLC.