Objective To investigate the mechanism of glucose-regulated protein 78 (GRP78) on the proliferation and invasion of nasopharyngeal carcinoma (NPC) cells CNE1. Methods Specimens were collected from 56 newly diagnosed NPC patients without chemo/radiotherapy (40 males and 16 females) and 50 chronic nasopharyngitis patients (38 males and 12 females) from June 2018 to June 2019. Immunohistochemistry was used to detect the expression of GRP78 in NPC tissue and chronic nasopharyngitis tissue. Cell experiments were divided into control group (CNE1 cells were routinely cultured without external intervention), negative control (NC) group (CNE1 cells were transfected with LvGFP-Puro-GRP78-NC, and then routinely cultured), and Sh-GRP78 group (CNE1 cells were transfected with LvGFP-Puro-GRP78, and then routinely cultured). 48h after transfection, intracellular green fluorescent protein (GFP) was observed under fluorescence microscope and the expression of GRP78 mRNA was detected by polymerase chain reaction (PCR). In cells of each group, Brdu labeling was used to detect the proliferation ability, Transwell chamber assay to detect the invasion ability, tubule formation experiment to detect the angiogenesis ability, double luciferase assay to analyze the relationship between GRP78 and matrix metalloproteinase-2 (MMP-2), MMP-9, and Western blot to detect the expression levels of GRP78, MMP-2 and MMP-9. Results The expression of GRP78 in NPC specimens was significantly higher than that the in chronic nasopharyngitis ones (P<0.05). Compared with the control groups, the abilities of proliferation, invasion and migration, as well as blood vessel formation in the Sh-GRP78 group were significantly enhanced, and the differences were all statistically significant (all P<0.05). Dual luciferase assay showed that MMP-2 and MMP-9 were the target genes of GRP78. Compared with the control group and the NC group, the expression levels of GRP78, MMP-2 and MMP-9 in the Sh-GRP78 group were significantly increased, and the differences were statistically significant (all P<0.05). Conclusion GRP78 is highly expressed in NPC, and GRP78 targets to regulate the expressions of MMP-2 and MMP-9 to enhance the proliferation, invasion and angiogenesis of CNE1 cells.