γ-valerolactone　(GVL)　is　a　key　value-added　chemical　catalytically　produced　from　levulinic　acid　(LA),　an　important　biomass　derivative　platform　chemical.　Here　an　ultra-efficient　3D　Ru　catalyst　generated　by　in　situ　reduction　of　RuZnOx　nanoboxes　is　reported;　the　catalyst　features　a　well-defined　structure　of　highly　dispersed　in　situ　oxide-derived　Ru　(IOD-Ru)　clusters　(≈1 nm　in　size)　spatially　confined　within　the　3D　nanocages　with　rich　mesopores,　which　guarantees　a　maximized　atom　utilization　with　a　high　exposure　of　Ru　active　sites　as　well　as　a　3D　accessibility　for　substrate　molecules.　The　IOD-Ru　exhibits　ultrahigh　performance　for　the　hydrogenation　of　LA　into　GVL　with　a　record-breaking　turnover　frequency　(TOF)　up　to　59400　h−1,　14　times　higher　than　that　of　the　ex　situ　reduction　of　RuZnOx　nanoboxes　catalyst.　Structural　characterizations　and　theoretical　calculations　collectively　indicate　that　the　defect-rich　and　coordination-unsaturated　IOD-Ru　sites　can　boost　the　activation　of　the　carbonyl　group　in　LA　with　a　significantly　lowered　energy　barrier　of　hydrogenation.　©　2023　Wiley-VCH　GmbH.