Decoration of an axial coordination ligand (ACL) on the active metal site is a highly effective and versatile strategy to tune activity of single-atom catalysts (SACs). However, the regulation mechanism of ACLs on SACs is still incompletely known. Herein, we investigate diversified combinations of ACL-SACs, including all 3d–5d transition metals and ten prototype ACLs. We identify that ACLs can weaken the adsorption capability of the metal atom (M) by raising the bonding energy levels of the M−O bond while enhancing dispersity of the d orbital of M. Through examination of various local configurations and intrinsic parameters of ACL-SACs, a general structure descriptor σ is constructed to quantify the structure–activity relationship of ACL-SACs which solely based on a few key intrinsic features. Importantly, we also identified the axial ligand descriptor σ_ACL, as a part of σ, which can serve as a potential descriptor to determine the rate-limiting steps (RLS) of ACL-SACs in experiment. And we predicted several ACL-SACs, namely, CrN₄-, FeN₄-, CoN₄-, RuN₄-, RhN₄-, OsN₄-, IrN₄- and PtN₄-ACLs, that entail markedly higher activities than the benchmark catalysts of Pt and IrO₂ for oxygen reduction reaction and oxygen evolution reaction, respectively, thereby supporting that the general descriptor σ can provide a simple and cost-effective method to assess efficient electrocatalysts.