Precise regulation of interfacial redox processes at the micro/nanoscale is critical for achieving sensitive and durable electrochemical sensing in complex aqueous environments. Here, we report a biomimetic electrochemical sensor featuring a coordination-confined and self-renewing Cu+/Cu2+ redox microinterface for ultrasensitive uranyl (UO22+) detection. Inspired by copper-containing ceruloplasmin, nitrogen- and oxygen-rich coordination domains are integrated with a three-dimensional conductive polymer framework to stabilize transient Cu+ species and enable reversible redox cycling under aqueous conditions. Upon selective coordination with amidoxime ligands, UO22+ perturbs the coordination-confined Cu+/Cu2+ redox equilibrium through interfacial electron redistribution, leading to a concentration-dependent decrease in the oxidation current. The sensor achieves an ultralow detection limit of 0.0011 μg L−1, a rapid response time below 3 min, and over 104 -fold selectivity against coexisting ions. Notably, the redox interface can be efficiently regenerated via electrochemical polarization or chemical re-chelation, maintaining stable performance over 50 sensing cycles with minimal signal loss. Validation in natural seawater samples shows excellent agreement with Inductively Coupled Plasma–Mass Spectrometry (ICP–MS) analysis (relative standard deviation < 4.65%). This work demonstrates a generalizable strategy for transforming unstable redox species into renewable sensing nodes through micro/nano-confined interfacial regulation, offering new opportunities for sustainable electrochemical monitoring of radionuclides and other metal ions.