Oral biofilms harbour Gram-negative bacterial antigens lipopolysaccharide (LPS) that have long been recognised in oral cancer progression. Gram-positive bacterial surface-associated adhesive lipoteichoic acid (LTA) antigens are also present within the oral microbiome, but their role in oral homeostasis is less well understood. Here, we investigated the impact of combined LPS and LTA treatment on oral cancer cells compared to stimulation by LPS alone. Oral cancer cell lines SCC25 and Cal 27 were treated in comparison to the normal oral cell line, OKF6. The real-time Glo MT cell viability assay was used to evaluate bacterial antigen stimulation indices. Cell proliferation following antigen stimulation was assessed by clonogenic assays. RT-qPCR, Western blotting and Phosphokinase arrays were employed to identify the mechanism of bacterial antigen-stimulated cell proliferation. We found that LPS and LTA treatment increased the proliferation of oral cancer cells (p ≤ 0.001). The combined antigen stimulation led to a decrease in phosphorylated p53 and β-catenin and to an increase in phosphorylated PI3K compared to cells stimulated with LPS only (p ≤ 0.001). Therefore, we conclude that combined antigen stimulation results in increased cancer cell proliferation by promoting the activity of major proto-oncogenic signalling pathways. Thus, this project highlights the role of Gram-positive bacteria in the progression of oral cancer and incites future studies on the oral microbiome to broaden their scope in oral cancer.