Nowadays, the carbon-neutral trend and the crude oil crisis have brought natural gas into increasing focus. However, heavy-duty engines fueled by natural gas have been plagued by thermal efficiency and knocking limitation problems. Well-structured charge motions can enhance thermal efficiency and concurrently mitigate knock, however, there is a lack of comprehensive work involving charge motions. In this paper, numerical simulation is employed to investigate the impact of charge motion on knock and thermal efficiency under high load conditions for a heavy-duty spark-ignition natural gas engine. The findings indicate that in the configuration with intense swirl, the diminished turbulent kinetic energy (TKE) at the combustion chamber’s base lessens the convective heat exchange between the fresh charge and the heated exhaust gases, resulting in a noticeable high-temperature zone and triggering hot spots. In configurations with inclined swirl and strong tumble motion, the extensive tumble motion near the spark plug region close to top dead center leads to an asymmetric flame front shape, determining the location of hotspots. The research also revealed that excessive tumbling motion and TKE can increase the likelihood of engine knock, while appropriate cylinder charge motion can improve the knock resistance of the engine to some extent, the maximum reduction in knocking intensity can reach 92.5%. The optimized combustion systems can significantly improve the initial combustion rate, shorten the ignition delay period, and advance the combustion center. With the combined effects of ignition timing and charge motion, the total indicated specific power per unit of fuel mass is increased in the optimized systems. Compared to the original combustion system, the indicated thermal efficiency within the knocking boundary can be improved by 1.11%.