A new approach of NOx reduction in the compression ignition engine is introduced in this work. The previous research has shown that during the combustion stage, the high temperature ignition tends to occur early at the near stoichiometric region at which combustion temperature is high and majority of NOx is formed; Therefore, it would be desirable to burn the leaner region first and then the near stoichiometric region, which inhibits the temperature rise of the near stoichiometric region and consequently suppresses the formation of NOx. Such inverted ignition sequence requires mixture with inverted phi-sensitivity. Fuel selection is performed based on the criterion of strong ignition T-sensitivity, large heat capacity, and large heat of vaporization (HoV). Thermodynamic analysis is performed in conjunction with ignition delay analysis to illustrate the selected fuel’s potential to generate mixture with inverted phi-sensitivity. 3-D engine CFD simulation is conducted with the selected fuel. The low NOx operation with inverted ignition sequence is computationally demonstrated at heavy-duty-relevant overall equivalence ratio.