Hepatitis B surface antigen (HBsAg) seroclearance during treatment is associated with a better prognosis among patients with chronic hepatitis B (CHB). Significant gaps remain in our understanding on how to predict HBsAg seroclearance accurately and efficiently based on obtainable clinical information. This study aimed to identify the optimal model to predict HBsAg seroclearance. We obtained the laboratory and demographic information for 2,235 patients with CHB from the South China Hepatitis Monitoring and Administration (SCHEMA) cohort. HBsAg seroclearance occurred in 106 patients in total. We developed models based on four algorithms, including the extreme gradient boosting (XGBoost), random forest (RF), decision tree (DCT), and logistic regression (LR). The optimal model was identified by the area under the receiver operating characteristic curve (AUC). The AUCs for XGBoost, RF, DCT, and LR models were 0.891, 0.829, 0.619, and 0.680, respectively, with XGBoost showing the best predictive performance. The variable importance plot of the XGBoost model indicated that the level of HBsAg was of high importance followed by age and the level of hepatitis B virus (HBV) DNA. Machine learning algorithms, especially XGBoost, have appropriate performance in predicting HBsAg seroclearance. The results showed the potential of machine learning algorithms for predicting HBsAg seroclearance utilizing obtainable clinical data.