Real-time　monitoring　of　hydroxyl　radical　(⋅OH)　generation　is　crucial　for　both　the　efficacy　and　safety　of　chemodynamic　therapy　(CDT).　Although　⋅OH　probe-integrated　CDT　agents　can　track　⋅OH　production　by　themselves,　they　often　require　complicated　synthetic　procedures　and　suffer　from　self-consumption　of　⋅OH.　Here,　we　report　the　facile　fabrication　of　a　self-monitored　chemodynamic　agent　(denoted　as　Fc-CD-AuNCs)　by　incorporating　ferrocene　(Fc)　into　β-cyclodextrin　(CD)-functionalized　gold　nanoclusters　(AuNCs)　via　host–guest　molecular　recognition.　The　water-soluble　CD　served　not　only　as　a　capping　agent　to　protect　AuNCs　but　also　as　a　macrocyclic　host　to　encapsulate　and　solubilize　hydrophobic　Fc　guest　with　high　Fenton　reactivity　for　in　vivo　CDT　applications.　Importantly,　the　encapsulated　Fc　inside　CD　possessed　strong　electron-donating　ability　to　effectively　quench　the　second　near-infrared　(NIR-II)　fluorescence　of　AuNCs　through　photoinduced　electron　transfer.　After　internalization　of　Fc-CD-AuNCs　by　cancer　cells,　Fenton　reaction　between　redox-active　Fc　quencher　and　endogenous　hydrogen　peroxide　(H2O2)　caused　Fc　oxidation　and　subsequent　NIR-II　fluorescence　recovery,　which　was　accompanied　by　the　formation　of　cytotoxic　⋅OH　and　therefore　allowed　Fc-CD-AuNCs　to　in　situ　self-report　⋅OH　generation　without　undesired　⋅OH　consumption.　Such　a　NIR-II　fluorescence-monitored　CDT　enabled　the　use　of　renal-clearable　Fc-CD-AuNCs　for　efficient　tumor　growth　inhibition　with　minimal　side　effects　in　vivo.　©　2023　Wiley-VCH　GmbH.