Intracerebral hemorrhage (ICH) is a life-threatening subtype of cerebral stroke with high morbidity and mortality; however, effective treatment for ICH is still lacking. Adiponectin (APN) is a a kind of fat-derived plasma protein with beneficial effects in cerebrovascular disorders. In this study, we aimed to investigate the protective effects of recombinant APN peptide (APNp) on brain injury after ICH in adult male C57BL/6J mice and further explored the underlying molecular mechanisms of these effects. APNp treatment exerted dose-dependent neuroprotective effects including improved neurological function, decreased brain edema, reduced neural apoptosis, and alleviated blood-brain barrier (BBB) disruption in ICH mice. We found the massive accumulation of APNp on reactive astrocytes around brain microvessels under hemorrhage conditions by immunofluorescence analysis. mRNA sequencing (mRNA-seq) and transcriptome analysis indicated that APNp significantly attenuated the inflammatory response and mitochondrial respiratory dysfunction in astrocytes. Further study revealed that this process was, at least in part, reliant on the inhibition of Drp1-mediated excessive mitochondrial fission. More specifically, APNp increased AMP-activated protein kinase (AMPK) activation-dependent Drp1 serine 637 (S637) phosphorylation, which inhibited the translocation of Drp1 to the mitochondrial membrane and reduced mitochondrial fragmentation and the production of mitochondrial superoxide, ultimately attenuating inflammatory brain injury induced by hemorrhage. In conclusion, we propose APNp as a potential therapeutic agent for ICH. We provide the first mechanistic evidence that APNp can modulate Drp1-mediated mitochondrial fission, which then contributes to alleviating astrocyte-derived inflammation.