Tumor-associated autoantibodies can be used as biomarkers for detecting different types of cancers. Our objective was to use machine learning techniques to predict high-risk cases of oral squamous cell carcinoma (OSCC) with salivary autoantibodies. The optimal model was using eXtreme Gradient Boosting (XGBoost) with the area under the receiver operating characteristic curve (AUC) of 0.765 (p < 0.01). Thus, applying machine learning model to early detect high-risk cases of OSCC could assist the clinic treatment and prognosis.