Nanoparticles　and　antibiotics　are　toxic　to　humans　and　ecosystems,　and　they　inevitably　coexist　in　the　wastewater　treatment　plants.　Hence,　the　co-existence　effects　and　stress　mechanism　of　copper　(II)　oxide　nanoparticles　(CuO　NPs)　and　ciprofloxacin　(CIP)　on　simultaneous　nitrification,　endogenous　denitrification　and　phosphorus　removal　(SNEDPR)　by　aerobic　granular　sludge　(AGS)　were　investigated　here.　The　co-existence　stress　of　5　mg/L　CuO　NPs　and　5　mg/L　CIP　resulted　in　the　synergistic　inhibitory　effect　on　nutrient　removal.　Transformation　inhibition　mechanisms　of　carbon　(C),　nitrogen　(N)　and　phosphorus　(P)　with　CuO　NPs　and　CIP　addition　were　time　-dependent.　Furthermore,　the　long-term　stress　mainly　inhibited　PO43--P　removal　by　inhibiting　phosphorus　release　process,　while　short-term　stress　mainly　inhibited　phosphorus　uptake　process.　The　synergistic　inhibitory　effect　of　CuO　NPs　and　CIP　may　be　due　to　the　changes　of　physicochemical　characteristics　under　the　co-existence　of　CuO　NPs　and　CIP.　This　further　altered　the　sludge　characteristics,　microbial　community　structure　and　functional　metabolic　pathways　under　the　long-term　stress.　Resistance　genes　analysis　exhibited　that　the　co-existence　stress　of　CuO　NPs　and　CIP　induced　the　amplification　of　qnrA　(2.38　folds),　qnrB　(4.70　folds)　and　intI1　(3.41　folds)　compared　with　the　control　group.