In the current study, a 0D/1D engine model built in the commercial code GT-Suite was coupled with the Electronic Control Unit (ECU) model created in the Simulink environment, aiming to more accurately predict the interaction of the engine and aftertreatment system (ATS) operating parameters, both during steady-state and transient maneuvers. After a detailed validation based on extensive experimental data from a heavy-duty commercial diesel Internal Combustion Engine (ICE), the engine model was fine-tuned and the 0D predictive diesel combustion model, DIPulse, was calibrated to best predict the combustion process, including engine-out NOx emissions. For correct prediction of the engine’s behavior in transient operations, the complete control strategy of the air path, including boost, exhaust gas recirculation (EGR), main and pilot Start of Injection (SOI), injection pressure, and exhaust flap, was implemented in the Simulink environment. To demonstrate the predictive capability of the model, a hot World Harmonized Transient Cycle (WHTC) was simulated, obtaining good agreement with the experimental data both in terms of emissions and performance parameters, confirming the reliability of the proposed approach. Finally, a case study on possible fuel consumption improvement through thermal insulation of the exhaust manifold, exhaust ports, and turbocharger was carried out.