This paper presents analytical and measured results on the effects of injection pattern design on piston thermal management in an Opposed-Piston, Two-Stroke (OP2S) diesel engine. The OP2S architecture investigated in this work comprises two opposing pistons forming an asymmetric combustion chamber with two opposing injectors mounted on the cylinder wall. This unique configuration offers opportunities to tailor the injection pattern to control the combustion heat flux and resulting temperatures on the piston surfaces while optimizing combustion simultaneously. This study utilizes three-dimensional (3D) computational fluid dynamics (CFD) with state-of-the-art spray, turbulence and combustion models that include detailed chemistry to simulate the in-cylinder combustion and the associated flame/wall interactions. In addition, the measurements comprise a real-time thermocouple system, which allows for up to 14 locations to be monitored and recorded on the intake and exhaust pistons.The CFD results are shown to predict the measured performance and emissions characteristics with very good correlation. Using the CFD model results, hot spot areas on the piston surfaces-resulting from impingement of the injection plumes during the combustion event-are computed. A proprietary telemetry system using thermocouples at key locations on the piston is deployed to measure the effects of injector clocking and injection spray angle on the piston temperatures. It is demonstrated that the trends in the computed hot spot areas for different injection patterns correlate well with trends in the measured temperatures. Furthermore, the investigations show that the clocking angle and the spray angle are two critical levers that can be optimized using CFD simulations for piston thermal management in the OP2S configuration. The results of this investigation demonstrate the effectiveness of experimentally correlated combustion-CFD simulations to unlock the potential of the OP2S configuration for improved piston thermal management.