Background: Dexmedetomidine (DEX) is an α₂-adrenergic agonist widely used for intravenous sedation. Its pharmacological properties suggest autonomic modulatory effects; however, these remain insufficiently characterized during operative procedures. This pilot study compared autonomic responses to surgical stress of DEX and propofol (PPF) during third molar extraction using the Analgesia Nociception Index (ANI), a heart rate variability-derived marker of autonomic balance. Methods Adults aged ≥18 years undergoing extraction of mandibular third molars under intravenous sedation were prospectively enrolled. Sedation was maintained with either DEX or PPF infusion following a small pre-induction dose of midazolam. ANI was continuously recorded using a High-Frequency Variability Index module, with a 240-s moving average considered equivalent to ANI. The primary outcome was the minimum ANI value within each predefined 5-min intraoperative interval; percent change from baseline (%Δ