In the pursuit of manufacturing intricate components for the nuclear industry, we developed a novel Zr63.2Cu36.8 (wt.%) alloy via vacuum melting for brazing applications involving equiatomic high-entropy alloys (HEA) of CoCrFeMnNi and zircaloy (Zr-3). We systematically investigated the influence of various brazing parameters on microstructure evolution and shear properties. Furthermore, we established a comprehensive understanding of the relationship between the lattice structure of interfacial products, residual stress, and fracture behavior in HEA/Zr-Cu/Zr-3 joints. Our findings revealed that under specific conditions (1010 °C for 10 min), the reaction products in HEA/Zr-Cu/Zr-3 joints consisted of lamellar HEAP/lamellar Zr(Cr,Mn)2, granular (Zr,Cu)/Zr2(Cu,Ni,Co,Fe), bulk Zr(Cr,Mn)2, and Zrss. With increasing temperature and prolonged holding time, the layered HEAP and Zr(Cr,Mn)2 phases adjacent to the HEA substrates thickened, while the relative amounts of Zr2(Cu,Ni,Co,Fe) decreased, with a remarkable increase in ductile Zrss. Growth kinetics analysis of the reaction layer and EBSD analysis indicated that the HEAP phases exhibited a lower growth rate compared to the Zr(Cr,Mn)2 layer during brazing, and both phases exhibited random grain orientations. Particularly noteworthy was the precipitation of (Zr,Cu) within the layered Zr(Cr,Mn)2, which increased and coarsened with higher temperatures and extended durations. Finite element analysis and TEM analysis revealed higher residual stresses at the non-coherent Zr(Cr,Mn)2/HEAP interface with a lattice mismatch of 40.6%. The body-centered cubic (BCC) structural HEAP, composed of fine grains, effectively mitigated the concentrated residual stresses due to its superior plasticity. Moreover, micro-nanoscale close-packed hexagonal (HCP) precipitates (Zr,Cu) were distributed within the brittle Zr(Cr,Mn)2 phases, contributing to the overall strength improvement of the joints. Consequently, high-quality HEA/Zr-3 joints were achieved, featuring a maximum strength of 172.1 MPa, equivalent to approximately 62.6% of the yield strength of Zr-3. These results highlight the potential of Zr63.2Cu36.8 (wt.%) alloys in advanced brazing applications.