An advanced numerical investigation has been carried out in order to study the effect of multiple injection strategies on Caterpillar heavy-duty diesel engine emissions. Both different injected fuel percentages for each pulse and several dwells between main and post phase were investigated via computational fluid dynamics (CFD) and large eddy simulation (LES). Two sets of simulations were taken into account for 10% and 20% exhaust gas recirculation (EGR) fractions. In the first one, the main injection was split into two identical phases, while in the second one into three pulses. Within each set, three strategies were considered, increasing the amount of fuel injected during the main and concurrently decreasing the post pulse. Overall, 48 simulations were employed, since four different dwells between the last phase of the main and post injection were considered. Results show that the pollutant emissions minimization has been obtained for the Schemes injecting 65% and 70% of fuel for both two and three split strategies, but for different values of dwell. In fact, emissions very close to each other for NO x and particulate matter have been reached for these cases. Reductions of about −30% and −71% were respectively obtained for NO x and soot in comparison with experimental emissions related to the single injection case.