Nucleosome assembly protein 1-like 1 (NAP1L1) is significantly involved in the development of various cancers. However, its role in the molecular mechanism of nasopharyngeal carcinoma (NPC) remains undetermined. In this study, we detected the upregulated expression of NAP1L1 mRNA and protein levels by quantitative polymerase chain reaction and Western blot analysis in NPC cell lines. Results of the immunohistochemistry analysis of NPC tissue biopsies showed that upregulated NAP1L1 protein expression promoted NPC progression and negatively correlated with poor prognosis in NPC patients. Suppression of NAP1L1 expression by small interfering RNA (siRNA) or small hairpin RNA (shRNA) methods significantly decreased cell proliferation in vivo and in vitro. Mechanism analysis revealed that the regulation of cell growth was enriched by Gene Set Enrichment Analysis based on RNA sequencing data. Cell cycle-induced genes CCND1 and E2F1 were downregulated in NAP1L1 knockdown NPC cells. Reduced NAP1L1 suppressed the recruitment of hepatoma-derived growth factor (HDGF) and decreased its expression. Knockdown of HDGF reduced the expression of c-JUN, a key oncogenic transcription factor that can induce the expression of cyclin D1 (CCND1), reducing cell cycle progression and suppressing cell growth in NPC. Transfecting HDGF or c-JUN could reverse the growth-suppressive effects in NAP1L1-downregulated NPC cells. The data obtained in this study suggest that NAP1L1 acts as a potential oncogene by activating HDGF/c-JUN/CCND1 signaling in NPC.