The present study focused on the propagation of a hot thermal transient through a U-Bend, and the resulting thermal stresses this causes. The flow conditions are fully turbulent in a mixed convection regime. A coupled framework has been used to simulate the 3-D conjugate heat transfer between the fluid and solid domains, and subsequently compute the thermal stress within the solid domain. An empirical model is then used for the fatigue life prediction. Highly complex flow evolution has been observed. Significantly, the reversal of the Dean vortex pair due to buoyancy has been identified. This reversal causes steep wall temperature gradients, increases the thermal stress at the front and back part 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.