A　high‐efficiency　PtZnCd　nanozyme　was　screened　with　density　functional　theory　(DFT)　and　unique　d‐orbital　coupling　features　for　sensitive　enrichment　and　real‐time　analysis　of　CO‐releasing　molecule‐3　(CORM‐3).　Multicatalytic　sites　in　the　nanozyme　showed　a　high　reactivity　of　up　to　72.89 min−1　for　peroxidase　(POD)‐like　reaction,　which　was　2.2,　4.07,　and　14.67　times　higher　than　that　of　PtZn　(32.67 min−1),　PtCd　(17.89 min−1),　and　Pt　(4.97 min−1),　respectively.　Normalization　of　the　catalytic　sites　showed　that　the　catalytic　capacity　of　the　active　site　in　PtZnCd　was　2.962 U　μmol−1,　which　was　four　times　higher　than　that　of　a　pure　Pt　site　(0.733 U　μmol−1).　DFT　calculations　showed　that　improved　d‐orbital　coupling　between　different　metals　reduces　the　position　of　the　center　of　the　shifted　whole　d‐band　relative　to　the　Fermi　energy　level,　thereby　increasing　the　contribution　of　the　sites　to　the　electron　transfer　from　the　active　center,　accompanied　by　enhanced　substrate　adsorption　and　intermediate　conversion　in　the　catalytic　process.　The　potential　adsorption　principle　and　color　development　mechanism　of　CORM‐3　on　PtZnCd　were　determined,　and　its　practical　application　in　drug　metabolism　was　validated　in　vitro　and　in　zebrafish　and　mice　models,　demonstrating　that　transition‐metal　doping　effectively　engineers　high‐performance　nanozymes　and　optimizes　artificial　enzymes.