Synchrotron radiation real-time imaging technology was performed to in situ study the Cu–Ni cross-interaction in Cu/Sn/Ni solder joints under temperature gradient during soldering. The direction of temperature gradient significantly influenced the Cu–Ni cross-interaction. When Ni was the hot end, both Cu and Ni atoms could diffuse to the opposite interfaces, resulting in the occurrence of the Cu–Ni cross-interaction at both interfaces. The consumption of the Cu cold end was abnormally large, whereas that of the Ni hot end was limited. When Cu was the hot end, only Cu atoms could diffuse to the opposite interface, resulting in the occurrence of the Cu–Ni cross-interaction only at the cold end. The Cu hot end was seriously consumed, whereas the Ni cold end was still intact. The interfacial intermetallic compounds were always thicker at the cold end than at the hot end, especially at the Ni/Sn cold end. Cu imposed more damaging effect than Ni under temperature gradient. Based on the atomic fluxes, a model was proposed to discuss the effect of temperature gradient on the Cu–Ni cross-interaction and the interfacial reactions in the Cu/Sn/Ni solder joints.