Backgrounds <p>Intracerebral hemorrhage (ICH) is a destructive form of stroke with significant morbidity and mortality. We aimed to study the mechanism of carboxy terminus of hsp70-interacting protein (CHIP) in neurological functional recovery after ICH via ubiquitination modification of forkhead box protein O1 (FOXO1).</p> Methods <p>The ICH model was established. CHIP, FOXO1, and triggering receptor expressed on myeloid cells-1 (TREM-1) were overexpressed by lentivirus injection, and their expression levels were detected. The proteasome inhibitor was injected for deubiquitination. The pathological changes were detected by hematoxylin and eosin staining assay. The neurological function was assessed by forelimb placement test, corner turn test, and Longa EZ method. The brain water content was calculated by the dry–wet weight method. The cell apoptosis was detected by terminal deoxynucleotidyl transferase dUTP nick-end labeling. The interaction between CHIP and FOXO1, FOXO1 and TREM-1 was detected by co-immunoprecipitation and dual-luciferase reporter gene assay. The ubiquitination of FOXO1 was detected.</p> Results <p>CHIP expression was compensatively elevated, and FOXO1 and TREM-1 were highly expressed in ICH mice. CHIP overexpression reduced brain injury, promoted neurological functional recovery, and alleviated apoptosis. CHIP promoted FOXO1 protein degradation to inhibit its expression by ubiquitination modification. FOXO1 bound to the TREM-1 promoter region to promote TREM-1 transcription. FOXO1 or TREM-1 overexpression partially reversed the promotive effect of CHIP overexpression on neurological functional recovery in mice after ICH.</p> Conclusion <p>CHIP overexpression reduced brain injury and improved neurological functional recovery in mice after ICH by promoting the ubiquitination and degradation of FOXO1 to inhibit TREM-1 expression.</p>