Being an energy source of another origin, the compression ignition (CI) engine’s typical design parameters might not suit Simarouba oil methyl ester (SuOME). Present experimental investigation targets are determining the effects of engine design parameters, including fuel injection pressure and nozzle geometry, on the engine, concerning performance and emissions such as carbon monoxide (CO), unburnt hydrocarbon (HC), oxides of nitrogen (NOx), and smoke opacity, with SuOME as fuel. Comparisons of brake thermal efficiency (BTE) and different emissions from the engine tailpipe were performed for different fuel injection pressures and a number of injector holes and diameter of orifices were opened in the injector to find the optimum combination to run the engine with SuOME. It was observed that the combined effect of an increase in injection pressure of 240 bar from 205 bar, and increasing number of injector holes from three to six with reduced injector hole diameters from 0.2 to 0.3 mm, recorded higher brake thermal efficiency with reduced emission levels for the SuOME mode of operation compared to the baseline standard operation with SuOME. For 240 bar compared to 205 bar of injection pressure (IP) for SuOME, the BTE increased by 2.35% and smoke opacity reduced by 1.45%. For six-hole fuel injectors compared to three-hole injectors, the BTE increased by 3.19%, HC reduced by 9.5%, and CO reduced by 14.7%. At 240 bar IP, with the six-hole injector having a 0.2 mm hole diameter compared to the 0.3 mm hole diameter, the BTE increased by 5%, HC reduced by 5.26%, CO reduced by 25.61%, smoke reduced by 10%, while NOx increased marginally by 0.27%. Hence, the six-hole FI, 240 IP, 0.2 mm FI diameter holes are suitable for diesel engine operation fueled by Simarouba biodiesel.