Objective To investigate the mechanisms underlying the role of osteopontin (OPN) in the growth, invasion, and hepatic metastasis of Echinococcus multilocularis via the epidermal growth factor receptor (EGFR) pathway. Methods The C57 mouse model with E. multilocularis infection was established. In one month after infection, 100 model mice were randomly divided into 4 groups. Mice in the Lv-EmOPN-734 group and the Lv3-NC group were injected with lentivirus Lv-EmOPN-734 and Lv3-NC (empty plasmid), respectively, while mice in the PBS group were injected with PBS. The blank control group did not receive any injection. Liver tissues of mice at 5 days after injection were collected from the Lv-EmOPN-734 groups, and were prepared as cryo-sections to observe the entry of lentivirus into the liver tissue. The body weight, liver weight, and the liver volume were recorded at 1, 2, 3 and 4 months after infection, the liver tissue infected with E. multilocularis was examined, and HE staining was performed to examine the metastasis of E. multilocularis. qRT-PCR was performed to detect the transcription level of OPN mRNA, and Western blotting performed to analyze the expression of AKT and ERK (OPN and EGFR pathway molecules). Between-group analysis was made with t-test, and multi-group comparisons were performed with ANOVA. Results As observed in the frozen slices, lentivirus was mainly located in the inflammatory belt of hepatic lesion, external capsule and mucous layer cells. At 4 months after infection (3 months after virus injection), no metastasis was found in the Lv-EmOPN-734 group, with mild lesions of E. multiloculari, while in the other 3 groups, the liver surface was enveloped by E. multiloculari tissue and showed different degrees of angiogenesis. On 2 to 4 months after infection (1 to 3 months after injection of virus), the liver wet weight and volume of the Lv3-NC group, the PBS group and the blank control group were all significantly higher than those of the Lv-EmOPN-734 group (P < 0.01). The body weight of mice in the 4 groups persistently increased during 1 to 3 months after infection, and in 4 months after infection, the body weight in the Lv-EmOPN-734 group continued to increase to (41.300 ± 1.252) g, while the remaining 3 groups showed decreased body weight (P < 0.01). HE staining showed that the lung metastasis of E. multilocularis occurred in the Lv3-NC group 4 months after infection. The qRT-PCR results showed that the relative mRNA transcription level of the Lv-EmOPN-734 group was 1.44 ± 0.54, lower than the Lv3-NC group (16.62 ± 0.61), PBS group (15.45 ± 1.11) and blank control group (16.36 ± 0.79) (P < 0.01). Western blotting results showed that the relative expression of OPN, P-EGFR, P-ERK and P-AKT in the E. multilocularis tissue of the Lv-EmOPN-734 group were (0.18 ± 0.01), (0.30 ± 0.04), (0.33 ± 0.04), and (0.25 ± 0.02), respectively, all significantly lower than those in the other 3 groups (P < 0.01), while no significant difference was found of relative expression of EGFR, ERK and AKT, compared with the other three groups (P > 0.05). Conclusion OPN may promote growth and development of E. multilocularis via the EGFR pathway. When EmOPN is knocked down, E. multilocularis grows slowly in the liver, and no distant transfer occurs, suggesting that OPN may be a potential therapeutic target for E. multilocularis.