The reduction in nitrogen oxides (NOx) emissions from heavy-duty diesel engines requires the development of more advanced combustion and control technologies to minimize the total cost of ownership (TCO), which includes both the diesel fuel consumption and the aqueous urea solution used in the selective catalytic reduction (SCR) aftertreatment system. This drives an increased need for highly efficient and clean internal combustion engines. One promising combustion strategy that can curb NOx emissions with a low fuel consumption penalty is to simultaneously reduce the in-cylinder gas temperature and pressure. This can be achieved with Miller cycle and by lowering the in-cylinder oxygen concentration via exhaust gas recirculation (EGR). The combination of Miller cycle and EGR can enable a low TCO by minimizing both the diesel fuel and urea consumptions.In this work, Miller cycle with late intake valve closing (IVC) and EGR technology were investigated on a single cylinder common rail heavy-duty diesel engine at high load operation of 24 bar net indicated mean effective pressure. The experiments were performed with a constant intake manifold pressure of 3 bar while optimizing the start of diesel injection to keep the peak in-cylinder pressure limit of 180 bar. The aqueous urea solution consumption in the SCR aftertreatment system was estimated to evaluate the effectiveness of the strategies in terms of TCO. The calculation was based on the engine-out NOx emissions and the Euro VI NOx limit. The results revealed that the use of the Miller cycle without EGR reduced NOx emissions by 35% and the net indicated efficiency by 4% when compared to the case with the baseline IVC at −178 crank angle degrees (CAD) after top dead center (ATDC). The introduction of 8%EGR decreased the levels of NOx by 54% while maintaining similar net indicated efficiency at the baseline IVC. The combination of Miller cycle with an IVC at −127 CAD ATDC and an EGR rate of 8% achieved the best trade-off between NOx and ISFC, decreasing the NOx levels by 57% and the fuel consumption by 1.6% compared to the baseline case. Soot emissions were maintained below the Euro VI limit of 0.01 g/kW h. Carbon monoxide emissions were maintained at low levels except for the combination of an IVC at −114 and an EGR rate of 8%. Unburned hydrocarbon emissions were slightly decreased with EGR and late IVCs likely due to relatively longer ignition delays and higher exhaust gas temperature. Overall, the analysis showed that the combination of Miller cycle with an IVC at −127 CAD ATDC and 8%EGR achieved the lowest total fluid consumption despite the reduction in net indicated thermal efficiency.