This in vivo study explored the impact of TUBB6 inhibition in intracerebral hemorrhage (ICH), focusing on its effects on hematoma volume, microtubule stability, inflammation, neuronal preservation, and sensorimotor recovery. Sprague-Dawley rats was used to induce ICH by collagenase injection into the right striatum, followed by administration of TUBB6 antisense oligonucleotide (ASO) or Control ASO directly into the hematoma site 3 h post-ICH. Outcomes measured included hematoma volume, microtubule stability (acetylated α-tubulin), levels of inflammatory cytokines, mitogen-activated protein kinase (MAPK) pathway activity, neuronal degeneration (Fluoro-Jade C staining), and cell integrity (Cresyl Violet staining). Functional recovery was assessed using neurological severity scores (mNSS), corner turn, forelimb-placing, and rotarod tests, with body weight tracked for up to 28 days. TUBB6 expression increased with the severity of hemorrhage in the ICH models. TUBB6 ASO significantly reduced hematoma volume at 24- and 72-h post-ICH, restored acetylated α-tubulin levels, suppressed MAPK signaling pathway, and decreased pro-inflammatory markers with increased IL-10. TUBB6 ASO also reduced neuronal degeneration and improved cell viability. In terms of functional outcomes, the TUBB6 ASO + ICH group exhibited reduced mNSS scores, improved body weight maintenance, and better performance on corner turn, forelimb-placing and rotarod tests compared to the Control ASO + ICH group. TUBB6 ASO treatment demonstrated therapeutic potential in a rat model of ICH by reducing hematoma volume, stabilizing microtubules, modulating the MAPK signaling pathway, and mitigating inflammation. It also preserved neuronal integrity and enhanced sensorimotor recovery, suggesting its effectiveness as a therapeutic approach to improve ICH outcomes.