Objective: The purpose of this study was to investigate the effect of β-glucosidase (GBA) knockdown on the malignant progression of cisplatin (DDP) -resistant ovarian cancer cells, and to explore the mechanism of its regulation of epidermal growth factor receptor (EGFR) signaling pathway. Methods: A2780/DDP cells were divided into three groups: Con group (blank control), si-NC group (transfected with negative control si-NC), si-GBA group (transfected with si-GBA) and NSC 228155 group ( transfected with si-GBA and treated with 2 μmol/L NSC 228155 ). The protein expression levels of GBA, E-cadherin, N-cadherin, Vimentin, EGFR, p38 MAPK, phosphorylated (P)-p38 MAPK, ERK and (P)-ERK were detected by Western blot. The expression of GBA was measured by RT-qPCR in relative terms. To evaluate the cellular proliferative activity, migratory potential, and invasive capacity, we conducted CCK-8 proliferation assays, plate clonogenic assays, scratch wound healing assays, and Transwell migration tests. Results: Compared with the A2780 group, the protein expression level and mRNA relative expression of GBA in the A2780/DDP group were significantly increased (P<0.05). Compared with Con group and si-NC group, the proliferation activity, the number of cloned cells, the number of cloned cells and the number of transmembrane cells in si-GBA group were significantly decreased (P<0.05). There was a significant increase in the expression of E-cadherin (P<0.05), accompanied by a notable decrease in the expression levels of Vimentin, N-cadherin, and EGFR (P<0.05). Additionally, the ratios of phosphorylated p38 MAPK to total p38 MAPK (P-p38 MAPK/total p38 MAPK) and phosphorylated ERK to total ERK (P-ERK/total ERK) also exhibited significant downregulation (P<0.05). Compared with si-GBA group, the proliferation activity, the number of cloned cells, the number of cloned cells and the number of transmembrane cells in NSC 228155 group were significantly increased (P<0.05). A notable decrease was observed in the expression of E-cadherin (P<0.05), whereas there was a significant upregulation in the expression levels of Vimentin, N-cadherin, and EGFR (P<0.05). Additionally, the ratios of phosphorylated p38 MAPK to total p38 MAPK (P-p38 MAPK/p38 MAPK) and phosphorylated ERK to total ERK (P-ERK/ERK) also demonstrated a marked increase (P<0.05). In the nude mouse xenograft experiment, compared with the blank control group, the volume and weight of the transplanted tumor in the blank control+DDP group were significantly reduced (P<0.05). In comparison to the negative control group, a statistically significant reduction was observed in both the volume and weight of the transplanted tumors in the group that received DDP in addition to the negative control+DDP group (P<0.05). Compared with the knockdown group, the volume and weight of transplanted tumors in the knockdown+DDP group were significantly reduced (P<0.05). In contrast to both the blank control group and the negative control group, the knockdown group exhibited a statistically significant reduction in both the volume and weight of the transplanted tumors (P<0.05). Similarly, when compared to the blank control+DDP group and the negative control+DDP group, the knockdown+DDP group demonstrated a notable decrease in the volume and weight of the transplanted tumors (P<0.05). Conclusion: The knockdown of GBA significantly inhibits the proliferation, migration, and invasion of DDP-resistant OC)cells, and suppresses the growth of subcutaneous xenografts of A2780/DDP cells in nude mice. The mechanism may be achieved by inhibiting the EGFR/MAPK/ERK signaling pathway.