Background <p>Patients with oral tumors undergoing free-flap reconstruction require postoperative sedation to improve endotracheal tube tolerance and prevent emergence agitation. While remimazolam offers theoretical hemodynamic advantages over dexmedetomidine, clinical evidence in this context remains limited. This trial compared the efficacy and safety of both agents for sedation after microvascular reconstruction.</p> Methods <p>In this randomized, double-blind trial (September 2021–November 2022), 60 patients were enrolled. Upon PACU admission, patients received continuous infusions of remimazolam (0.25&#xa0;mg·kg⁻¹·h⁻¹) or dexmedetomidine (0.4&#xa0;µg·kg⁻¹·h⁻¹), titrated to a Ramsay Score of 2–3. The primary outcome was PACU emergence agitation incidence (RASS ≥ + 2). Secondary outcomes included delirium, pain, nausea/vomiting, sleep quality, hospital stay, and complications.</p> Results <p>​The final analysis included 57 patients (remimazolam <i>n</i> = 29, dexmedetomidine <i>n</i> = 28) due to consent withdrawal.​​ Emergence agitation incidence was comparable (27.6% vs. 25.0%, <i>p</i> &gt; 0.999; risk difference 2.6% [95% CI: − 21.5–26.7%]). ​Remimazolam significantly reduced colloid use in PACU (3.4% vs. 32.1%, <i>p</i> = 0.005).​​ No significant differences in secondary outcomes (delirium, pain scores, nausea/vomiting, hospital stay).</p> Conclusions <p>Remimazolam and dexmedetomidine demonstrated equivalent efficacy in preventing emergence agitation. ​The significantly reduced colloid requirement with remimazolam suggests enhanced hemodynamic stability, potentially benefiting flap perfusion.​​ Combined with its rapid-offset profile, remimazolam is a viable alternative for postoperative sedation in microvascular reconstruction.</p> Trial registration <p>Chinese Clinical Trial Registry, <a href="http://www.chictr.org.cn">www.chictr.org.cn</a>, ChiCTR2100048342. Registered on 05/07/2021.</p>