In　this　work,　we　exploited　the　synergy　between　homogeneous　and　heterogeneous　catalysis　for　the　efficient　and　selective　activation　of　H2O2.　The　homogeneous　catalyst　contained　a　very　trace　amount　of　Fe2+　(0.26　ppm),　which　is　lower　than　the　international　effluent　discharge　standard　for　Fe　(0.50　ppm).　The　heterogeneous　catalyst　was　composed　of　holey　graphitic　carbon　nitride　(g-C3N4)　nanosheets　carrying　highly　dispersed　single　atoms　(Mn,　Ni,　or　Cu).　Mechanistic　studies　revealed　that　the　strong　interaction　between　single　metal　sites　and　H2O2　forms　two　adsorption　configurations　(HOO-　and　H(O-O)-),　which　trigger　the　generation　of　different　reactive　oxygen　species　(ROS).　The　heterogeneous　Mn-C3N4　catalyst　provided　single　Mn-N3　sites　that　activated　H2O2　to　produce　O2　by　forming　HOO-Mn-N3,　while　the　adjacent　Fe2+　quickly　reduced　the　generated　O2　to　˙O2−,　which　can　efficiently　remove　organic　pollutants　and　inactivate　Escherichia　coli　under　neutral　conditions.　The　single-atom　Mn-C3N4,　in　addition,　provided　photoactive　electrons　that　drive　the　efficient　cycling　of　the　homogeneous　Fe2+/Fe3+　catalyst　(which　is　the　rate-determining　step)　under　very　trace　Fe2+　input.　By　coupling　homogeneous　and　heterogeneous　catalysis,　an　excellent　and　advanced　oxidation　process　with　potential　for　large-scale　application　is　reported　in　this　work;　the　findings　also　shed　light　on　the　theoretical　aspects　of　the　efficient　and　selective　activation　of　H2O2　at　the　atomic　level.　©　2024　The　Royal　Society　of　Chemistry.