Background <p>Oral squamous cell carcinoma accounts for over 90% of oral malignancies and remains a major global public health concern. Our previous study identified <i>Porphyromonas gingivalis</i> (<i>P. gingivalis</i>) as a key microbial factor in oral squamous cell carcinoma initiation and progression. However, the precise mechanisms by which <i>P. gingivalis</i> infection contributes to tumor progression remain unclear. Pathogens regulate exosome secretion during bacterial infection; therefore, this study aimed to investigate the role of exosomes from <i>P. gingivalis</i>-infected oral squamous cell carcinoma cells (Pg.Ex) in tumor progression.</p> Methods <p>We isolated exosomes using differential centrifugation. To elucidate the mechanisms by which Pg.Ex promote oral squamous cell carcinoma progression, microRNA sequencing was performed on exosomes isolated from <i>P. gingivalis</i>-infected and uninfected cells. Furthermore, the biological roles of Pg.Ex and exosomal miR-3648-1-p5 in oral squamous cell carcinoma tumor growth were examined in vitro and in vivo.</p> Results <p>We found that <i>P. gingivalis</i>-infected oral squamous cell carcinoma cells released lower concentrations and larger particle sizes of exosomes. Pg.Ex had lower levels of miR-3648-1-p5 and could be transferred to uninfected cells to promote the malignant phenotype of oral squamous cell carcinoma cells, in vitro and in vivo.</p> Conclusions <p>These findings reveal an unknown connection between low exosomal miR-3648-1-p5 expression in <i>P. gingivalis</i>-infected oral squamous cell carcinoma cells and oral squamous cell carcinoma progression. Therefore, targeting Pg.Ex and miR-3648-1-p5 may present a promising therapeutic strategy for the treatment of oral squamous cell carcinoma.</p>