Fuels originating from the gasoline production stream with high volatility and low aromatic content have shown great potential to reduce cradle-to-grave greenhouse gas emissions and criteria pollutants under mixing-controlled combustion in compression ignition (CI) engines. As global demand for diesel rises and CO2 emission targets fall, an incentive for methods of burning gasoline and other light end fuels as efficiently as possible emerges. In this study, a computational fluid dynamics (CFD) guided combustion system optimization was conducted for a model year 2013 Cummins ISX15 heavy-duty diesel engine with a higher reactivity fuel in mind. The primary goal was to utilize the higher volatility and lower sooting tendency of the fuel for improved fuel efficiency while maintaining engine-out NOx within production levels. The gasoline-like fuel used in this study has an anti-knock index (AKI) of 58, and the model was developed using the multi-dimensional CFD software package, CONVERGE. The initial and boundary conditions were generated from a well-validated one-dimensional GT-Power model. Model predictions were validated against experimental results generated using the stock engine hardware and showed very good agreement. For the design optimization, the main variables included piston bowl geometry, compression ratio (CR), injector configuration, injection timing and charge air motion. A comprehensive design of experiments (DoE) study was performed at different operating conditions on the supercomputer Mira to accelerate the development of an optimized fuel-efficiency focused design while maintaining the engine-out NOx and soot emissions levels of the stock engine. Compared to the baseline production combustion system, the optimized results showed a significant improvement in closed-cycle, indicated specific fuel consumption (ISFC) across different simulated engine speed and load points. When combined with modified injector configurations (i.e., spray angle, number of nozzle holes, and nozzle hydraulic flow rate), the optimized piston bowl designs showed better in-cylinder air utilization and shorter combustion duration, thereby leading to improved fuel efficiency. In particular, increasing the injector hydraulic flow rate (larger nozzle diameter) was found to be beneficial by shortening the combustion duration while producing a higher in-cylinder combustion temperature for enhanced soot oxidation. In addition to the soot reduction due to the gasoline-like fuel’s high volatility and low aromatic content, this temperature effect led to a further decrease in soot emissions in contrast to traditional diesel fuel in the same scenario. Increasing compression ratio from 18.9 to 20.5 was also crucial for improving the fuel efficiency. A systematic parametric study of the design variables was also conducted to understand the fuel effects in the current heavy-duty mixing-controlled combustion systems.