The　coordination　microenvironment　modulation　of　single-atom　catalysts　(SACs)　based　on　p-block　metals　holds　promise　for　excavating　their　enormous　potential　in　electrochemical　CO2-to　CO　conversion.　Guided　by　the　instructive　theoretical　calculations　over　serial　asymmetric　coordination　microenvironments,　herein,　a　novel　Pb　SAC　with　highly　asymmetric　coordination　microenvironment　(Pb-N2SV)　is　developed.　Namely,　the　Pb　atom　is　coordinated　with　two　N　atoms,　one　S　atom　and　one　vacancy　nearby.　With　the　breaking　of　coordination　symmetry,　the　obtained　Pb-N2SV　shows　excellent　ECR　performance　with　97.3%　Faradaic　efficiency　of　CO　at　−0.47 V,　and　long-term　stability　of　33 h,　which　exceeds　the　vast　majority　of　main-group　SACs.　More　importantly,　in　situ　spectroscopy　and　density　functional　theory　(DFT)　studies　unveil　that　the　S　doping　in　Pb　SAC　can　significantly　improve　electron　localization　around　Pb　sites　to　facilitate　*COOH　intermediate　adsorption,　while　the　introduction　of　vacancy　defect　nearby　the　Pb　sites　can　function　as　a　synergistic　modulation　on　the　electronic　structure　for　favorable　*CO　intermediate　desorption,　which　jointly　contributes　to　achieve　the　suitable　adsorption　energy　for　reaction　intermediates　to　boost　the　ECR　process.　As　an　expandability,　this　approach　will　be　widely　used　to　construct　SACs　with　unique　coordination　microenvironment　for　other　challenging　catalysis.　©　2023　Wiley-VCH　GmbH.