Photo-driven　cross-coupling　of　o-arylenediamines　and　alcohols　has　emerged　as　an　alternative　for　the　synthesis　of　bio-active　benzimidazoles.　However,　tackling　the　key　problem　related　to　efficient　adsorption　and　activation　of　both　coupling　partners　over　photocatalysts　towards　activity　enhancement　remains　a　challenge.　Here,　we　demonstrate　an　efficient　interface　synergy　strategy　by　coupling　exposed　oxygen　vacancies　(VO)　and　Pd　Lewis　acid　sites　for　benzimidazole　and　hydrogen　(H2)　coproduction　over　Pd-loaded　TiO2　nanospheres　with　the　highest　photoredox　activity　compared　to　previous　works　so　far.　The　results　show　that　the　introduction　of　VO　optimizes　the　energy　band　structure　and　supplies　coordinatively　unsaturated　sites　for　adsorbing　and　activating　ethanol　molecules,　affording　acetaldehyde　active　intermediates.　Pd　acts　as　a　Lewis　acid　site,　enhancing　the　adsorption　of　alkaline　amine　molecules　via　Lewis　acid-base　pair　interactions　and　driving　the　condensation　process.　Furthermore,　VO　and　Pd　synergistically　promote　interfacial　charge　transfer　and　separation.　This　work　offers　new　insightful　guidance　for　the　rational　design　of　semiconductor-based　photocatalysts　with　interface　synergy　at　the　molecular　level　towards　the　high-performance　coproduction　of　renewable　fuels　and　value-added　feedstocks.　©　2024　Wiley-VCH　GmbH.