The interaction in the ZrB2–Ni system with change in the ZrB2 content from 3.5 to 75 wt.% has been studied. It is shown that the process occurs through the contact melting mechanism, leading to the formation of a liquid phase, wetting the substrate with a contact angle of about 50°, even at 1250°C. The liquid phase interacts with the substrate and crystallizes with time as more refractory compounds are formed. The structure and phase composition of the reaction products are determined by the ratio of alloy components, representing double, triple, and more complex compounds based on the crystalline lattices of Zr–Ni intermetallides. The eutectic point is found at 13% ZrB2 in the alloy. The eutectic nature of the ZrB2–Ni quasibinary phase diagram restricts the upper temperature limit for application of the alloys and associated materials in friction joints of fuel equipment. Considering that they may undergo solid-phase interaction, the upper temperature limit is 1000°C.