A design optimization campaign was conducted to search for improved combustion profiles that enhance gasoline compression ignition in a heavy-duty diesel engine with a geometric compression ratio of 17.3. A large-scale design of experiments approach was used for the optimization, employing three-dimensional computational fluid dynamics simulations. The main parameters explored include geometric features, injector specifications, and swirl motion. Both stepped-lip and re-entrant bowls were included in order to assess their respective performance implications. A total of 256 design candidates were prepared using the software package CAESES for automated and simultaneous geometry generation and combustion recipe perturbation. The design optimization was conducted for three engine loads representing light to medium load conditions. The design candidates were evaluated for fuel efficiency, emissions, fuel–air mixing, and global combustion behavior. Simulation results showed that the optimum designs were all stepped-lip bowls, due to improvements in fuel–air mixing, as well as reduced heat loss and emissions formation. Improvements in indicated specific fuel consumption of up to 3.2% were achieved while meeting engine-out NOx emission targets of 1–1.5 g/kW · h. Re-entrant bowls performed worse compared to the baseline design, and significant performance variations occurred across the load points. Specifically, the re-entrant bowls were on par with the stepped-lip bowls under light load conditions, but significant deteriorations occurred under higher load conditions. As a final task, selected optimized designs were then evaluated under full-load conditions.