<p>Optimizing oxygenation for patients necessitates a delicate balance between sufficient oxygen delivery and mitigating the potential hazards of hyperoxemia. We hypothesized that integrating Oxygen Reserve Index (ORi) monitoring would effectively reduce intraoperative hyperoxemia compared to reliance solely on pulse oximetry. This single-center randomized controlled trial included multiple trauma patients with ASA class 3 or higher undergoing general anesthesia. FiO₂ adjustments to 0.5 started at T0 with arterial blood gas analysis (ABGA) every 30-minutes. Patients were randomized into Group O (ORi monitoring) and Group N (pulse oximetry). In Group O, FiO₂ was reduced if ORi &gt; 0.05; unchanged if ORi was 0-0.05. Group N decreased FiO₂ if SpO₂ was 100%, unchanged if SpO₂ was &lt; 99%, and increased FiO₂ by 0.05 until SpO₂ reached 95% or above. 54 participants were randomized, and 51 analyzed. Group O demonstrated a significantly higher percentage of normoxemia (80 ≤ PaO₂ &lt; 120 mmHg) (64.4% vs. 40.4%, <i>P</i> = 0.002) across 181 ABGAs. Although baseline PaO₂ (T1) values were comparable within moderate hyperoxemia, at T2, only Group O achieved normoxemia, with consistently lower PaO₂ values at T2, T3, and T4 compared to Group N. ORi values in Group O consistently trended lower from T1 to T4. The positive correlation between PaO₂ and ORi was reaffirmed, establishing cut-off values for PaO₂ ≥ 120mmHg and ≥ 150mmHg at 0.06 and 0.22, respectively. Simultaneous ORi and pulse oximetry reduce intraoperative hyperoxemia through safe and meticulous protocol adherence in patients.</p>