Fibroblast growth factor-inducible 14 (Fn14) has been reported to play an oncogene role in many types of cancer. However, its biological functions in small-cell lung cancer (SCLC) remain unknown. The aim of this study is to investigate the roles of Fn14 in the cell growth and chemoresistance of SCLC and its possible molecular mechanism. Expression of Fn14 was examined in 51 cases of SCLC tissues by immunohistochemistry. Overexpression or knockdown of Fn14 was carried out in SCLC multidrug-resistant cell lines (H69AR and H446AR) and the parental cell lines (H69 and H446) to assess its influence on cell growth and chemoresistance. The results showed that Fn14 was expressed in 50.98% (26/51) of SCLC. Overexpression of Fn14 was associated with the poor pathologic stage of SCLC (P < 0.05 by the Fisher's exact test) and the shorter survival time (by the Kaplan-Meier method). Enforced expression of Fn14 in H69 and H446 cells promoted cell growth and enhanced multidrug resistance by decreasing cell apoptosis and increasing G2-phase cell accumulation. Inhibition of Fn14 expression using Fn14 shRNA in H69AR and H446AR cells inhibited cell growth and sensitized cancer cells to chemotherapeutic drugs by increasing drug-induced cell apoptosis accompanied by G1, S phase arrest. Furthermore, elevated expression of Fn14 in H69 and H446 cells can lead to increased expression of Bcl-xl and activity of nuclear factor-κB (NF-κB). Similar results were observed by Fn14 knockdown H69AR and H446AR cells. Bcl-xl expression regulated by Fn14 was dependent on NF-κB activation. Our results suggest that Fn14 modulates cell growth and drug resistance by upregulating Bcl-xl expression through the NF-κB pathway. All findings provide insight into the Fn14 signaling mechanism and Fn14 may be a potentially novel target for interfering with cancer growth and chemoresistance in SCLC.