The purpose of this study is to investigate the performance, in-cylinder combustion, and emissions of the MTE660E heavy-duty diesel engine using 3D CFD simulation. The CFD simulation model based on AVL FIRE software was developed to numerically investigate the performance, in-cylinder combustion, and emissions of the MTE660E engine. The AVL model was validated against empirical data. The 6-cylinder MTE660E engine was operated under a constant excess air ratio of 1.75 and at 1600 rpm engine speed. The geometry and lattice design of the MTE660E engine were simulated to provide a computationally efficient approach. The AVL model was validated against experimental data and the error between the measured and calculated value of combustion characteristics and emissions was acceptable (R2> 90 %), error <5.6 %). Design Expert software was used to optimize the dependent variables (peak chamber temperature, brake mean effective pressure, engine torque, engine thermal efficiency and emissions of NOx) according to the studied variables (injection time and fuel injection quantity) based on response surface methodology. The results show that the recommended injecting time of 342 °C and the specific amount of fuel lead to better combustion efficiency, resulting in high engine performance and low emissions. The specific fuel consumption was highest at 2200 rpm with a 50 % load, while the lowest SFC level was observed at 1750 rpm with a 100 % load. The maximum value of NOx emissions was observed at full load. The findings show that the optimization of the injection timing and fuel injection quantity can effectively enhance the performance of the MTE660E engine. The study provides valuable insights into improving combustion efficiency, resulting in greater performance and reduced emissions without requiring expensive overhaul. It has potential applications in automotive and commercial transportation industries, thereby reducing fuel consumption and emissions.