The continuous growth in total health expenditure (THE) has become a social issue of common concern in most countries. In China, the total health expenditure (THE) is maintaining a rapid growth trend that is higher than that of the economy, which has become increasingly obvious in the 21st century and has brought a heavy burden to the government and residents. To analyze the main driving factors of THE in China in the 21st century and establish a predictive model, gray system theory was employed to explore the correlation degree between THE and nine hot topics in the areas of the economy, population, health service utilization, and policy using national data from 2000 to 2018. Additionally, a New Structure of the Multivariate Gray Prediction Model of THE was established and compared with the traditional grey model and widely used BP neural network to evaluate the prediction effectiveness of the model. We concluded that the Chinese government and society have played a crucial role in reducing residents’ medical burden. Besides this, the improved economy and aging population have increased the demand for health services, leading to the continual increase in THE. Lastly, the improved NSGM(1,N) model achieved good prediction accuracy and has unique advantages in simulating and predicting THE, which can provide a basis for policy formulation.