Decarbonizing long-haul goods transportation poses a substantial challenge. High-efficiency natural gas (NG) engines, which retain the efficiency of a diesel engine but reduce the carbon content of the fuel, offer substantial potential for near-term greenhouse gas (GHG) reductions. A fast-running model that can predict engine performance, GHG and air pollutant emissions is critical to assessing this approach for different applications and vehicle drivetrain configurations. This paper presents the development, validation and application of an engine system model that adapts GT-SUITE™’s phenomenological DI-Pulse predictive model to predict the performance and emissions of a 6-cylinder NG engine using a high pressure direct-injection combustion process. The model includes the engine air exchange system, enabling the prediction of the engine and in-cylinder conditions and overall performance over transient drive cycles. The engine model with a fixed set of calibration parameters captures the complex high-pressure direct injection combustion process and generates time-resolved parameters that are fed into a coupled machine learning model to predict emissions, including nitrogen oxide (NOx) and methane (CH4) emissions. While the 1-D model’s predictions for CH4 were not accurate, coupling the 1-D engine model with a machine learning model has been shown to substantially improve the estimation of CH4 emissions and allow accurate prediction of engine total GHG emissions over different duty cycles. The model has been validated using transient engine dynamometer data and is then applied to assess performance and emissions over several regulatory and real-world long-haul drive cycles. The model showed an average error of less than 5% in steady operation. Cumulative errors of NOx and CH4 emissions in studied cycles were also less than 10%. The results showed that CH4 share in total GHG emissions ranges from 0.2% to 1.4% over various drive cycles. By predicting engine performance and emissions, the developed combined model has considerable potential for use in engine evaluation studies, especially when combined with new technologies across different duty cycles.