Ischaemic stroke is a leading cause of death and serious long-term disability worldwide, yet overall availability of current treatments is limited. The downstream events resulting from spontaneous or pharmacological reperfusion lead to an imbalance in the production of harmful reactive oxygen species (ROS) over endogenous antioxidant mechanisms. Thus, treatments that can reduce this imbalance could limit the extent of injury resulting from ischaemic stroke. In this work, we have used oxidation-responsive cross-linked polymeric nanoparticles (NPs), known as poly(propylene sulfide) (PPS) NPs, to scavenge ROS and subsequently reduce post-stroke inflammation and damage. The potential of PPS- NPs for ischaemic stroke therapy was evaluated in vitro and in a mouse model of stroke (middle cerebral artery occlusion, MCAo). In vitro results show that PPS-NPs are highly antioxidative and anti-inflammatory, whilst exhibiting negligible cytotoxicity. NPs administered intravenously rapidly accumulated in ischaemic brain as visualised through fluorescence imaging, reduced infarct volume, blood-brain barrier damage, neuronal loss, and neuroinflammation as determined by immunohistochemistry, and improved functional outcome as determined through behavioural analyses. Crucially, we show that the therapeutic time window for administration of PPS-NPs extends from 0.5 h to 3 h, a clinically relevant time window for stroke. Our findings provide strong evidence that these NPs may prove to be an effective antioxidant therapy for ischaemic stroke patients.