Foot-and-mouth disease virus (FMDV) causes an acute and highly contagious viral disease in cloven-hoofed animals and uses integrin αvβ1, αvβ3, αvβ6, αvβ8, and heparan sulfate proteoglycans (HSPGs) receptors to enter the host cell. Although heparan sulfates have been observed to play a role in binding many viruses to the host cell surface, there is no information in the literature about which member of this polysaccharide family is involved in FMDV binding. Syndecan-1 (SDC1), a member of the heparan sulfate proteoglycan family, exhibits a close association with the integrin family of receptors. In this study, FMDV-insensitive SW480 cells were sensitized by human SDC1 gene transfection. Integrin αvβ6 was used as a positive control group. The SW480 cell line was separately transfected with SDC1, integrin β6, and control plasmids. Following the transfection, the gene expression levels of SDC1 and integrin β6 were quantified using qPCR. In the final stage of the study, the sensitivity to FMDV was examined by monitoring the cytopathic effect (CPE) after the virus inoculation of the gene-transfected cells. This study demonstrated an increase in the expression of the SDC1 gene and the integrin β6 gene post-transfection in SW480 cells. Moreover, FMDV CPE was detected in wells containing cells transfected with both the β6 gene and SDC1, although the effect was higher in the wells transfected with the β6 gene. In conclusion, the in vitro evidence suggests that the SDC1 transmembrane protein could serve as a potential cellular receptor candidate for FMDV.