F-box/WD repeat-containing protein 7 (FBW7) is a member of the F-box protein family that regulates cell cycle progression and cell growth and differentiation. FBW7 also functions as a tumor suppressor. A cisplatin (CDDP)-based multidrug chemotherapy regimen is standard for nasopharyngeal carcinoma (NPC), but drug resistance is an increasing problem. Here, we evaluated the relationship between FBW7 and multidrug resistance-associated protein (MRP), and its correlation with drug resistance in NPC, and explored the mechanism underlying drug resistance to CDDP in this disease. We used cell viability assays, Western blotting, and small interfering RNA (siRNA) interference to investigate the underlying mechanism underlying CDDP resistance in a NPC cell line. The expression of FBW7 and MRP was detected by Western blotting after siRNA interference in the CDDP-resistant NPC cell line, CNE2-CDDP. The 3-(4 5-dimethyl-2-thiazolyl)-2 5-diphenyl-2-H-tetrazolium bromide (MTT) assay was used to evaluate drug sensitivity of various types of antitumor drugs, including paclitaxel (PCX), CDDP, fluorouracil (5-FU), and vincristine (VCR). We found that siRNA-mediated upregulation of FBW7 significantly increased CDDP chemosensitivity. The IC50 values of CDDP in siRNA-FBW7-CNE2-CDDP and FBW7-CNE2-CDDP-NC cells were 2.485 ± 0.155 and 4.867 ± 0.442 μmol/mL, respectively. The IC50 values of PCX, CDDP, 5-FU, and VCR were significantly decreased in siRNA-FBW7-CNE2 than in FBW7-CNE2-NC (3.46 ± 0.14 vs. 46.21 ± 6.03 μmol/mL; 3.76 ± 0.54 vs. 39.45 ± 0.96 μmol/mL; 2.14 ± 1.67 vs. 28.76 ± 1.89 μmol/mL; 4.43 ± 0.89 vs. 87.90 ± 3.45 μmol/mL, respectively). The IC50 of CDDP was significantly less in siRNA-FBW7-CNE2-CDDP than in FBW7-CNE2-CDDP-NC. The level of FBW7 expression in CNE2 cells was correlated with CDDP chemosensitivity. siRNA-mediated upregulation of FBW7 expression downregulated the expression of MRP, significantly increasing drug sensitivity in CNE2 cells.