The present study focused on the propagation of a hot thermal transient through a U-bend and the resulting thermal stresses. The flow conditions were fully turbulent in a mixed-convection regime. A coupled framework was used to simulate the 3D conjugate heat transfer between the fluid and solid domains and subsequently compute the thermal stress within the solid domain. An empirical model was then used for the fatigue life prediction. Highly complex flow evolution was observed. Significantly, the reversal of the Dean vortex pair due to buoyancy was identified. This reversal causes steep wall-temperature gradients, increases the thermal stress at the front and back parts of the two bends, and generates a large stress region at the bottom of the near-horizontal section, which leads to a fatigue life reduction of the U-bend.