Maximizing　the　catalytic　activity　of　single-atom　and　nanocluster　catalysts　through　the　modulation　of　the　interaction　between　these　components　and　the　corresponding　supports　is　crucial　but　challenging.　Herein,　guided　by　theoretical　calculations,　a　nanoporous　bilayer　WS2　Moiré　superlattices　(MSLs)　supported　Au　nanoclusters　(NCs)　adjacent　to　Ru　single　atoms　(SAs)　(Ru1/Aun-2LWS2)　is　developed　for　alkaline　hydrogen　evolution　reaction　(HER)　for　the　first　time.　Theoretical　analysis　suggests　that　the　induced　robust　electronic　metal–support　interaction　effect　in　Ru1/Aun-2LWS2　is　prone　to　promote　the　charge　redistribution　among　Ru　SAs,　Au　NCs,　and　WS2　MSLs　support,　which　is　beneficial　to　reduce　the　energy　barrier　for　water　adsorption　and　thus　promoting　the　subsequent　H2　formation.　As　feedback,　the　well-designed　Ru1/Aun-2LWS2　electrocatalyst　exhibits　outstanding　HER　performance　with　high　activity　(η10 = 19 mV),　low　Tafel　slope　(35 mV dec−1),　and　excellent　long-term　stability.　Further,　in　situ,　experimental　studies　reveal　that　the　reconstruction　of　Ru　SAs/NCs　with　S　vacancies　in　Ru1/Aun-2LWS2　structure　acts　as　the　main　catalytically　active　center,　while　high-valence　Au　NCs　are　responsible　for　activating　and　stabilizing　Ru　sites　to　prevent　the　dissolution　and　deactivation　of　active　sites.　This　work　offers　guidelines　for　the　rational　design　of　high-performance　atomic-scale　electrocatalysts.　©　2024　Wiley-VCH　GmbH.