Hand, foot, and mouth disease (HFMD) is an important public health problem and has received concern worldwide. Moreover, the coronavirus disease 2019 (COVID-19) epidemic also increases the difficulty of understanding and predicting the prevalence of HFMD. The purpose is to prove the usability and applicability of the automatic machine learning (Auto-ML) algorithm in predicting the epidemic trend of HFMD and to explore the influence of COVID-19 on the spread of HFMD. The AutoML algorithm and the autoregressive integrated moving average (ARIMA) model were applied to construct and validate models, based on the monthly incidence numbers of HFMD and meteorological factors from May 2008 to December 2019 in Henan province, China. A total of four models were established, among which the Auto-ML model with meteorological factors had minimum RMSE and MAE in both the model constructing phase and forecasting phase (training set: RMSE = 1424.40 and MAE = 812.55; test set: RMSE = 2107.83, MAE = 1494.41), so this model has the best performance. The optimal model was used to further predict the incidence numbers of HFMD in 2020 and then compared with the reported cases. And, for analysis, 2020 was divided into two periods. The predicted incidence numbers followed the same trend as the reported cases of HFMD before the COVID-19 outbreak; while after the COVID-19 outbreak, the reported cases have been greatly reduced than expected, with an average of only about 103 cases per month, and the incidence peak has also been delayed, which has led to significant changes in the seasonality of HFMD. Overall, the AutoML algorithm is an applicable and ideal method to predict the epidemic trend of the HFMD. Furthermore, it was found that the countermeasures of COVID-19 have a certain influence on suppressing the spread of HFMD during the period of COVID-19. The findings are helpful to health administrative departments.