AbstractSingle‐atom‐based Metal‐Organic Frameworks (MOFs) hold great promising candidates for heterogeneous catalysis, demonstrating outstanding catalytic activity and exceptional product selectivity. This is attributed to their optimal atom utilization, high surface energy, and the presence of unsaturated coordination environments. Here in, we have developed a nickel single‐atom catalyst (SAC) featuring Ni single atoms covalently attached to defect‐engineered Zr‐oxide clusters within the stable UiO‐66 (Universitetet i Oslo) framework, synthesized via a straightforward solution impregnation method (denoted as UiO‐66/Ni now onwards). The resulting UiO‐66/Ni catalyst, with a uniform distribution of nickel single atoms, exhibits remarkable stability and demonstrates exceptional performance in C−S coupling reactions of various aryl thiols and aryl halides, yielding desired products with outstanding catalytic activity and selectivity, regardless of electron‐donating or withdrawing substituents at room temperature and maintains robust stability even after six cycles. Advanced density functional theory calculations have been exploited to clarify the mechanism of C−S cross‐coupling for examining the influence of substituents on the aromatic ring of aryl thiols through free energy profiles. The collaborative action of nickel single atoms and the defects of UiO‐66 during the oxidative addition and reductive elimination steps facilitated the formation of energetically favorable C−S cross‐coupling products. This study offers valuable insights for the development of enhanced single atom‐based hybrid catalytic systems for heterogeneous coupling reactions.