In nuclear power systems, the structural integrity of piping is of great significance to the stable operation of the entire nuclear power unit. Down-horizontal (DH) piping is a stagnant branch pipe that connects to a main and is closed at the end. Due to the significant temperature difference between the fluid in the main pipe and the branch pipe, the thermal cycling phenomenon of periodic movement of the hot and cold interfaces may occur, which in turn causes thermal fatigue and structural failure of the pipeline. In this work, the temperature fluctuation characteristics and hydrodynamic behavior of the DH piping are investigated by numerical simulation, and the stress fluctuation is analyzed. The Large Eddy Simulation (LES) turbulence model is used to simulate the thermal cycling phenomenon in the DH piping, and grid independence work is carried out to verify the reliability of the network model. The effects of different thermo-hydraulic parameters on the fluid flow and heat transfer characteristics in the DH piping are analyzed, and the mechanisms of these parameters on the thermal fatigue behavior of the pipeline are also evaluated. The results show that both turbulence penetration depth and thermal cycling period are affected by the thermo-hydraulic parameters. The stress concentration is more evident at the intersection of the main and branch pipes, and there is a large stress on the inside of the elbow in the horizontal section.