Background: This study aimed to compare the effects of equipotent doses (one minimum alveolar concentration) of sevoflurane and desflurane on respiratory mechanics, haemodynamics and oxygenation in patients undergoing spinal surgery in the prone position. Methods: Fifty patients were randomised to receive either sevoflurane (n = 25) or desflurane (n = 25). Respiratory parameters (dynamic compliance (Cdyn); peak (Ppeak), mean (Pmean) and plateau (Pplateau) airway pressures; driving pressure (∆P); tidal volume; and dead space), haemodynamic parameters (heart rate (HR) and systolic, mean and diastolic arterial pressures) and oxygenation parameters were recorded intraoperatively at baseline, after prone positioning, during surgery, and after returning to the supine position. Results: Prone positioning led to significant increases in Ppeak and reductions in Cdyn in both groups (p < 0.05). Although Ppeak, Pmean, Pplateau and ∆P fluctuated intraoperatively, no intergroup differences were detected (p > 0.05). After returning to the supine position, respiratory mechanics approached baseline in both groups. Oxygenation (arterial oxygen pressure), ventilation (arterial carbon dioxide pressure), end-tidal carbon dioxide, and pH remained stable and comparable. Sevoflurane was associated with slightly greater decreases in arterial pressures, whereas HR was similar between groups. Conclusions: Both desflurane and sevoflurane maintained stable intraoperative respiratory mechanics, oxygenation, and haemodynamics in patients without pulmonary disease. Prone positioning increased Ppeak and decreased Cdyn similarly in both groups. Both agents appear safe for spinal surgery in the prone position. Clinical Trial Registration: This study was registered at ClinicalTrials.gov (NCT06118489).