[en] Highlights: • A Two-Stroke diesel engine for aircraft propulsion was modeled with a 0D/1D approach. • The results of the 0D/1D model are compared with those resulting from a 3D model. • The effect of several design and thermodynamic parameters have been analyzed. • Guidelines for the optimization of engine performance are provided. - Abstract: In Two-Stroke engines, the cylinder filling efficiency is antithetical to the cylinder scavenging efficiency; moreover, both of them are influenced by geometric and thermodynamic parameters characterizing the design and operation of both the engine and the related supercharging system. Aim of this work is to provide several guidelines about the definition of design and operation parameters for a Two-Stroke two banks Uniflow diesel engine, supercharged with two sequential turbochargers and an aftercooler per bank, with the goal of either increasing the engine brake power at take-off or decreasing the engine fuel consumption in cruise conditions. The engine has been modeled with a 0D/1D modeling approach. Then, the model capability in describing the effect of several parameters on engine performance has been assessed comparing the results of 3D simulations with those of 0D/1D model. The validated 0D/1D model has been used to simulate the engine behavior varying several design and operation engine parameters (exhaust valves opening and closing angles and maximum valve lift, scavenging ports opening angle, distance between bottom edge of the scavenging ports and bottom dead center, area of the single scavenging port and number of ports, engine volumetric compression ratio, low and high pressure compressor pressure ratios, air/fuel ratio) on a wide range of possible values. The parameters most influencing the engine performance are then recognized and their effect on engine thermodynamic behavior is discussed. Finally, the system configurations leading to best engine power at sea level and lowest fuel consumption in cruise conditions – respectively +42% and −7% with respect to baseline – have been determined implementing a multicriteria optimization procedure.