Objective This study aimed to investigate how β-glucosidase (GBA) knockdown affects malignant progression in cisplatin (DDP)-resistant ovarian cancer (OC) cells and the role of the EGFR signaling pathway. Methods The A2780/DDP cells were categorized into four groups, with one of them serving as blank control (Con) group, 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 mitogen-activated protein kinase (p38 MAPK), phospho (p)-p38 MAPK, extracellular regulated protein kinase (ERK) and p-ERK were detected through Western blot. The relative expression of GBA was evaluated through reverse transcription quantitative polymerase chain reaction. The proliferation activity, migration, and invasion potential were evaluated using cell counting kit-8 (CCK-8), plate clone formation, cell scratch healing, and Transwell migration assays. Thirty-six nude mice were divided into six groups (six mice per group): blank control (injected with normal saline), blank control + DDP (treated with DDP), negative control (injected with A2780/DDP cell suspension transfected with si-NC), negative control + DDP (injected with A2780/DDP cell suspension transfected with si-NC and treated with DDP), knockdown (injected with A2780/DDP cell suspension transfected with si-GBA), and knockdown + DDP groups (injected with A2780/DDP cell suspension transfected with si-GBA and treated with DDP). The tumor volume and weight of nude mice were evaluated. Results The relative protein and mRNA expression levels of GBA were significantly higher in the A2780/DDP group than in the A2780 group (P<0.05). Compared with estimates in the Con and si-NC groups, the proliferation activity, number of cloned cells, scratch repair rate, and number of transmembrane cells in the si GBA group were significantly lower (P<0.05). The abundance of E-cadherin expression exhibited a notable elevation (P<0.05), and expression levels of Vimentin, N-cadherin, and EGFR as well as the p-p38 MAPK/p38 MAPK and p-ERK/ERK ratios were significantly decreased (P<0.05). The proliferation activity, number of cloned cells, scratch repair rate, and the count of transmembrane cells and the expression level of E-cadherin in the NSC 228155 group were markedly higher and lower, respectively, than those in the si-GBA group (P<0.05), and the expression levels of Vimentin, N-cadherin, and EGFR as well as the ratios of p-p38 MAPK/p38 MAPK and p-ERK/ERK were significantly increased (P<0.05). In the nude mouse xenograft study, the tumor size and mass in the blank control + DDP group were notably smaller and lighter, respectively, compared to those in the blank control group (P<0.05). The tumor volume and weight were significantly lower in the negative control + DDP group than in the negative control group (P<0.05), significantly lower in the knockdown + DDP group than in the knockdown group (P<0.05), moreover, they were markedly reduced in the knockdown group in comparison to both the blank control and negative control groups (P<0.05). Compared with those in the blank control + DDP and negative control + DDP groups, the tumor volume and weight in the knockdown + DDP group were significantly reduced (P<0.05). Conclusions GBA knockdown suppresses the proliferation, migration, and invasion of DDP-resistant OC cells significantly as well as the growth of subcutaneous xenografts derived from A2780/DDP cells in nude mice. These effects may be mediated through the inhibition of the EGFR/MAPK/ERK signaling pathway.