Curcumin　(CUR)　is　a　natural　polyphenol　that　holds　promise　for　treating　ulcerative　colitis　(UC),　yet　oral　administration　of　CUR　exhibits　limited　bioavailability　and　existing　formulations　for　oral　delivery　of　CUR　often　suffer　from　unsatisfactory　loading　capacity.　This　study　presents　hydroxyethyl　starch-curcumin　microspheres　(HC-MSs)　with　excellent　CUR　loading　capacity　(54.52　%),　and　the　HC-MSs　can　further　encapsulate　anti-inflammatory　drugs　dexamethasone　(DEX)　to　obtain　a　combination　formulation　(DHC-MSs)　with　high　DEX　loading　capacity　(19.91　%),　for　combination　therapy　of　UC.　The　microspheres　were　successfully　engineered,　retaining　the　anti-oxidative　and　anti-inflammatory　activities　of　parental　CUR　and　demonstrating　excellent　biocompatibility　and　controlled　release　properties,　notably　triggered　by　α-amylase,　facilitating　targeted　drug　delivery　to　inflamed　sites.　In　a　mouse　UC　model　induced　by　dextran　sulfate　sodium,　the　microspheres　effectively　accumulated　in　inflamed　colons　and　both　HC-MSs　and　DHC-MSs　exhibited　superior　therapeutic　efficacy　in　alleviating　UC　symptoms　compared　to　free　DEX.　Moreover,　mechanistic　exploration　uncovered　the　multifaceted　therapeutic　mechanisms　of　these　formulations,　encompassing　anti-inflammatory　actions,　mitigation　of　spleen　enlargement,　and　modulation　of　gut　microbiota　composition.　These　findings　underscore　the　potential　of　HC-MSs　and　DHC-MSs　as　promising　formulations　for　UC,　with　implications　for　advancing　treatment　modalities　for　various　inflammatory　bowel　disorders.　©　2024　Elsevier　B.V.