The European Union made new CO2 limits for heavy-duty vehicles mandatory in 2019, aiming to reduce the average tailpipe CO2 emissions by 15% in 2025 and by 30% in 2030, relative to the 2019 baseline. To meet these challenges, new technologies are needed to further reduce the fuel consumption of new heavy-duty trucks (“tank to wheel”) by using more efficient engines. The present study shows the pathways to improve thermal efficiency through better mixture formation and air utilization. This is achieved by designing a new piston bowl shape that has been numerically optimized iteratively to improve the air/fuel mixing by carefully considering the interaction between the fuel spray plume and the piston bowl. The CFD model was calibrated using data from experimental studies with a heavy-duty single-cylinder diesel engine in best efficiency and rated power operation. Heat transfer and turbulence models are studied to determine their influence on the combustion process and NOx emissions. Indicated thermal efficiency and air utilization were used to evaluate the performance of the piston bowl shape. For three different bowl shapes, the fuel spray interaction with the piston bowl was investigated and compared with the base bowl shape with a compression ratio CR = 18.3. Moreover, the effect of a higher CR of 21 on performance and mixture formation was analyzed for the optimized bowl shape. The higher CR of 21 was attained by geometrically similar reduction of the optimized piston bowl. The results of the numerical and experimental investigations show that a CR of 21 leads to an increase in the indicated thermal efficiency of ∼ 3% in absolute values.