<p>Mixed-linker ZIF-8 metal–organic frameworks (MOFs) have garnered significant interest recently owing to their tunable structural and functional properties. In this study, histidine-functionalized ZIF-8 (His–ZIF-8) MOF was employed as a platform for Cu immobilization through mixed-linker synthesis followed by a post-synthetic copper-incorporation step. This approach led to the formation of a heterogeneous Cu(II)/His–ZIF-8 catalyst with a significant copper loading (13.13 wt%), in which Cu species are proposed to be immobilized in dual coordination environments, potentially involving coordination to the pendant α-amino and carboxylate groups of His together with possible partial Zn²⁺/Cu²⁺ transmetalation within the ZIF-8 framework. Following structural validation by complementary characterization techniques, the catalytic performance of the as-synthesized Cu(II)/His–ZIF-8 catalyst was methodically assessed in azide-alkyne cycloaddition (AAC) reactions. The catalyst exhibited excellent activity, producing 1,2,3-triazole derivatives in good to excellent yields (72–&gt;99%) under optimized conditions. The enhanced catalytic performance may be attributed to the cooperative effects of the proposed Cu immobilization pathways, which are expected to facilitate efficient Cu stabilization and dispersion within the MOF structure. Moreover, hot filtration, poisoning, and recyclability studies confirmed the predominantly heterogeneous character of the catalyst and its acceptable stability over four consecutive reuse cycles. This study delivers an effective strategy for designing His-functionalized ZIF-based catalysts capable of achieving strong metal immobilization through a proposed combination of coordination and framework interactions, with potential applicability to a range of catalytic transformations.</p>