Fibroblasts can transform into cancer-associated fibroblasts (CAFs) when continuously stimulated by cancer cells, thereby playing a crucial role in cancer progression. Growing evidence indicates that targeted therapy for CAF can influence tumor progression. Dihydroartemisinin (DHA) and artemether (ARM), semisynthetic derivatives of the natural compound artemisinin, have exhibited anticancer effects in various tumors. In this study, we found that tumor cells secreted platelet-derived growth factor-BB (PDGF-BB), which stimulated fibroblasts to transition into the CAF phenotype (cell phenotype and secretory phenotype). CAFs promote Cal-27 cell proliferation by secreting lactate. We focused on the mechanisms by which DHA and ARM affect the tumor-stroma interactions. These findings demonstrated that DHA and ARM effectively suppressed the secretion of PDGF-BB from Cal-27 cells, maintaining the normal state of hOMF and preventing the proliferative effect on Cal-27 cells. These findings were confirmed in xenograft models. Our study showed that artemisinin derivatives prevent the progression of oral tongue squamous cell carcinoma (OTSCC) by inhibiting the production of PDGF-BB in cancer cells to maintain the normal state of fibroblasts, thus providing a potential avenue for targeted OTSCC treatment.