This research aims to utilize gasoline compression ignition (GCI) to achieve low engine-out NOx emissions with high fuel efficiency, thereby offering a potential pathway to address the future low tailpipe NOx standard (0.027 g/kWh) proposed by the California Air Resources Board (CARB). The experimental work was conducted in a model year 2013 Cummins ISX15 heavy-duty diesel engine, covering a load range of 5 to 15 bar BMEP at 1375 rpm. The engine compression ratio was reduced from the production level of 18.9 to 15.7. In this work, four gasolines with research octane number (RON) ranging from 58 to 93 were studied. Overall, GCI operation resulted in enhanced premixed combustion, markedly improved NOx-soot tradeoffs, and similar fuel efficiency compared to diesel combustion. By employing a split fuel injection strategy and a lower fuel injection pressure, the RON80 gasoline showed improved fuel efficiency at 5 bar BMEP when compared to the baseline ULSD. Building on the experimental results and by performing closed-cycle, 3-D computational fluid dynamics (CFD) combustion simulations, engine thermal boundary conditions (i.e., pressure and temperature at intake valve closing, and EGR dilution level) tailored for low NOx GCI operation were developed, leading to improved benefits in fuel efficiency and soot over ULSD. These thermal boundary conditions were then used as inputs to 1-D engine cycle analysis to evaluate the performance with the existing air-handling system. Finally, an air system configuration customized for low NOx GCI operation was developed.