A closed-cycle computational model of a non-Wankel rotary engine was thoroughly investigated to achieve optimal efficiencies, in a multitude of loading conditions relevant to automotive and aeronautical applications. Computational fluid dynamics (CFD) modeling was conducted in CONVERGE CFD, targeting the operation of a single pre-chamber and downstream main chamber engine system, roughly from 100 crank angle degrees (CAD) before top dead center (bTDC) to 100 CAD after top dead center (aTDC). In the developed framework, optimization studies involved main decision variables, including the engine’s compression ratio (CR), the injector’s position within the pre-chamber, the injector’s nozzle hole count and nozzle hole diameters. Traditional and split-injection strategies for the introduction of diesel fuel into the pre-chamber were evaluated by varying spray-related parameters including total injected mass, injection pressure, start of injection(s), and injection duration(s). The main metrics used to evaluate the engine’s operation include (1) pre-chamber, main chamber, and overall combustion efficiencies and (2) closed-cycle average load performance determined by a relative indicated mean effective pressure metric. Additionally, the injected fuel phase state (liquid vs vaporized) and wall film thickness, if present, were used as performance metrics to determine fuel-air mixing success. Pre-chamber and main chamber maximum pressures were kept below 150 bar and injection pressures were limited at 1000 bar. As a result of this study, the best-performing cases demonstrated an overall combustion efficiency (ηc) that surpassed 90%, in both mid-load and high-load operating conditions.