Off-road heavy-duty diesel engines are equipped with complex aftertreatment systems to meet the stringent EPA Tier 4 emission standards. Traditionally, the thermal management of the aftertreatment system, aimed at efficiently reducing tailpipe emissions, involves controlling engine exhaust flow and temperature. However, this approach often leads to inefficient engine operation, especially in the low to mid-load regions, resulting in higher fuel consumption. Prior studies have highlighted the potential of cylinder deactivation (CDA) in reducing fuel consumption and increasing the exhaust temperature for thermal management in on-road applications. As the significance of controlling greenhouse gas (GHG) emissions from off-road machinery comes into focus, this study aims to experimentally demonstrate the fuel efficiency benefits and efficient aftertreatment thermal management achieved through CDA during high-speed operation on a Tier 4 level off-road heavy-duty diesel engine. In a typical off-road duty cycle, such as Non-Road Transient Cycle (NRTC), about 82.5% of cycle’s energy is produced in the engine speed range of 1750–2200 rpm, prompting investigation into the impact of CDA during high-speed operations. CDA results in airflow reductions and increased exhaust gas temperatures due to lower air–fuel ratio (AFR). The reduced airflow operation minimizes pumping work, allowing for higher open cycle efficiency, and thereby translating into lower fuel consumption. The study reveals a new finding: fuel benefits from CDA extend over a larger load range (up to 8.3 bar BMEP) during high-speed operation in off-road heavy-duty engines compared to findings in on-road heavy-duty engines. This phenomenon can be attributed to sufficient oxygen inducted during CDA operation, resulting from similar turbocharger speeds compared to all-cylinder firing operation, especially at high-loads, thereby maintaining particulate matter (PM) concentration within prescribed constraints. Steady-state test results demonstrate a reduction in fuel consumption from 33.7% at 0.4 bar to 1.4% at 8.3 bar BMEP, at 2100 rpm engine speed.