Non-alcoholic　fatty　liver　disease　(NAFLD)　has　become　a　globally　rising　issue　that　can　cause　liver-related　morbidity　and　mortality.　Recent　studies　have　revealed　that　a　high-fat　diet　(HFD)　highly　contributes　to　the　prevalence　and　progression　of　NAFLD　via　impacting　gut　microbiota　and　lipid　metabolism　signal　pathways.　Resveratrol　(RSV),　a　natural　bioactive　compound,　has　exhibited　potential　for　preventing　and　alleviating　NAFLD.　However,　due　to　the　poor　bioavailability　of　RSV,　its　strengths　and　underlying　mechanisms　for　NAFLD　therapeutic　potential　are　poorly　understood.　To　address　this,　we　utilized　Hydroxypropyl-beta-Cyclodextrin　(HBC)　to　encapsulate　RSV　to　enhance　its　water　solubility　and　conducted　prevention　and　intervention　experiments　in　HFDfed　mice.　The　results　showed　that　the　HBC　has　significantly　enhanced　the　water　solubility　of　RSV　by　250-fold　and　the　HBC-RSV　better　prevented　and　alleviated　the　liver　steatosis,　obesity　and　abnormal　lipid　metabolism　induced　by　HFD　than　RSV　alone.　Meanwhile,　combining　HFD　and　HBC-RSV　or　RSV　prevented　HFD　mice　progressing　to　NAFLD.　Besides,　further　investigation　indicated　that　RSV　could　resist　liver　injury　and　obesity　by　modulating　gut　microbiota,　raising　the　levels　of　short-chain　fatty　acids　(SCFAs)　and　activating　AMP-activated　protein　kinase　(AMPK)　signaling　pathway.　The　activated　pathway　down-regulated　sterol　receptor　element　binding　protein　1c　(SREBP1c)　and　acetyl-coenzyme　A　carboxylase　(ACC)　to　decrease　lipid　synthesis　and　up-regulated　peroxisome　proliferators-activated　receptor　&　alpha;　(PPAR　&　alpha;)　to　promote　the　fatty　acid　oxidation,　thus　preventing　NAFLD.　Our　findings　suggested　that　water　solubility-enhanced　RSV　beneficially　modulated　gut　microbiota,　altered　gut　microbiota-derived　SCFAs,　and　activated　lipid　metabolism　regulatory　pathways,　providing　potential　for　NAFLD　prevention　and　alleviation.