Farnesol is a catabolite within the isoprenoid/cholesterol pathway that has exhibited significant antitumor activity. Farnesol was recently identified as a quorum-sensing molecule produced by the fungal pathogen Candida albicans. In this study, we hypothesize that synthetic and Candida-produced farnesol can induce apoptosis in vitro in oral squamous cell carcinoma (OSCC) lines. Cell proliferation, apoptosis, mitochondrial degradation, and survivin and caspase expressions were examined. In addition, global protein expression profiles were analyzed using proteomic analysis. Results demonstrated significant decrease in proliferation and increase in apoptosis in cells exposed to farnesol and C. albicans culture media. Concurrently, protein expression analysis demonstrated a significant decrease in survivin and an increase in cleaved-caspase expression, whereas fluorescent microscopy revealed the presence of active caspases with mitochondrial degradation in exposed cells. A total of 36 differentially expressed proteins were identified by proteomic analysis. Among the 26 up-regulated proteins were those involved in the inhibition of carcinogenesis, proliferation suppression, and aging. Most notable among the 10 down-regulated proteins were those involved in the inhibition of apoptosis and proteins overexpressed in epithelial carcinomas. This study demonstrates that farnesol significantly inhibits the proliferation of OSCCs and promotes apoptosis in vitro through both the intrinsic and extrinsic apoptotic signaling pathways. In addition, we report for the first time the ability of Candida-produced farnesol to induce a similar apoptotic response through the same pathways. The capability of farnesol to trigger apoptosis in cancer cells makes it a potential tool for studying tumor progression and an attractive candidate as a therapeutic agent.