An increase in the carbon dioxide (CO2) concentration within a vehicle can lead to a decrease in air quality, resulting in numerous adverse effects on the human body. Therefore, it is very important to know the in-vehicle CO2 concentration level and to accurately predict a concentration change. The purpose of this research is to investigate in-vehicle concentration levels of CO2, comparing the accuracy of an autoregressive integrated moving average (ARIMA) model and a long short-term memory (LSTM) model in predicting the change in CO2 concentration. We conducted a field test to obtain in-vehicle original concentration data of CO2 while driving, establishing a prediction model of CO2 concentration with ARIMA and LSTM. We selected mean absolute percentage error (MAPE) and root mean squared error (RMSE) as the evaluation indicators. The findings indicate the following: (1) With the vehicle windows closed and recirculation ventilation mode activated, in-vehicle CO2 concentration increases rapidly. During testing, CO2 accumulation rates were measured at 1.43 ppm/s for one occupant and 3.52 ppm/s for three occupants within a 20 min driving period. Average concentrations exceeded 1000 ppm, so it is recommended to improve ventilation promptly while driving. (2) The MAPE of ARIMA and LSTM prediction results are 0.46% and 0.56%, respectively. The RMSE results are 19.62 ppm and 22.76 ppm, respectively. The prediction results demonstrate that both models effectively forecast changes in a vehicle’s interior environment CO2, but the prediction accuracy of ARIMA is better than that of LSTM. The research findings provide theoretical guidance to traffic safety managers in selecting suitable models for predicting in-vehicle CO2 concentrations and establish an effective in-vehicle ventilation warning control system.