The present study shows the impact of multiple injectors with distinctive spray and injection angles on engine efficiency, heat transfer (HT), and exhaust losses. It is well known from previous studies that multiple injectors, particularly two injectors, improve the air-fuel mixing while simultaneously reducing the HT losses by keeping hot reaction zones away from the combustion cylinder walls. However, it is unclear how the spray-to-spray, umbrella, and spray-orientation angles would impact the overall energy distribution in both the combustion cylinder and double compression expansion engine (DCEE) concept. In this study, three-dimensional (3D) Reynolds-averaged Navier-Stokes (RANS) simulations were conducted in a heavy-duty single-cylinder engine, comparing three-injectors and two different side-injectors cases with a baseline case of the centrally mounted single injector. To obtain the baseline case and validate the computational fluid dynamics (CFD) data, the engine was operated at 1200 rpm, and the fuel mean effective pressure (FuelMEP) of 40 bar using conventional diesel fuel was fixed. One-dimensional (1D) simulations then utilized the CFD-based in-cylinder pressure and rate of heat release (RoHR) traces to analyze the energy distribution of the DCEE concept. The CFD results show that the three-injectors and the best side-injectors case lead to 1.2%-points and 0.2%-points improvement of gross indicated efficiency (GIE) and heat losses reduction of 1.3%-points and 2%-points, respectively, compared to the baseline single-injector case. This is due to the longer injector-wall distance from the side injections, thereby reducing the HT losses, compared to the large coverage area of the high-temperature gases for the baseline case. The 1D results show that a high brake thermal efficiency (BTE) of 53% and 52.7% can be achieved with the three-injectors and the best side-injectors case, respectively, compared to 51.9% of the baseline case. This was due to the advanced combustion phasing, lower HT losses, and higher conversion efficiency of exhaust losses from the combustion cylinder into useful work in the expansion cylinder of the DCEE concept, resulting in an overall higher engine efficiency for multiple injectors.