Background and objective In general anesthesia, for certain surgical procedures in the prone position, patients often face increased airway pressures, reduced pulmonary and thoracic compliance, and restricted chest expansion, all of which can affect venous return and cardiac output, impacting overall hemodynamic stability. Positive end-expiratory pressure (PEEP) is used to address these issues by improving lung recruitment and ventilation while reducing stress on lung units. However, different PEEP levels also present risks such as increased parenchymal strain, higher pulmonary vascular resistance, and impaired venous return. Proper positioning and frequent monitoring are key to ensuring adequate oxygenation and minimizing complicationsarising from prolonged periods in the prone position. This study aimed to evaluate the effects of different PEEP levels (0 cmH2O, 5 cmH2O, and 10 cmH2O) in the prone position to determine the optimal setting for balancing improved oxygenation and lung recruitment against potential adverse effects. The goal is to refine individualized PEEP strategies beyond what is typically outlined in standard PEEP tables. We endeavored to examine the impact of different PEEP levels during pressure-controlled ventilation (PCV) on arterial oxygenation, respiratory parameters, and intraoperative blood loss in patients undergoing spine surgery in a prone position under general anesthesia. Methodology This randomized, single-blinded, controlled study enrolled 90 patients scheduled for elective spine fixation surgeries. Patients were randomized into three groups: Group A (PEEP 0), Group B (PEEP 5), and Group C (PEEP 10). Standardized anesthesia protocols were administered to all groups, with ventilation set to pressure-controlled mode at desired levels. PEEP levels were adjusted according to group allocation. Arterial blood gases were measured before induction, 30 minutes after prone positioning, and 30 minutes post-extubation. Arterial line insertion was performed, and dynamic compliance, mean arterial pressure (MAP), heart rate (HR), and intraoperative blood loss were recorded at regular intervals. Data were analyzed using SPSS Statistics version 21 (IBM Corp., Armonk, NY). Results Arterial oxygenation was significantly higher in Groups B (PEEP 5) and C (PEEP 10) compared to Group A (PEEP 0) at both 30 minutes post-intubation and post-extubation. Specifically, at 30 minutes post-intubation, arterial oxygenation was 142.26 ±24.7 in Group B and 154.9 ±29.88 in Group C, compared to 128.18 ±13.3 in Group A (p=0.002). Similarly, post-extubation arterial oxygenation levels were 105.1 ±8.28 for Group B and 115.46 ±15.2 for Group C, while Group A had levels of 97.07 ±9.90 (p<0.001). MAP decreased significantly in Groups B and C compared to Group A. Dynamic compliance was also improved in Groups B and C. Furthermore, intraoperative blood loss was notably lower in Group C (329.66 ±93.93) and Group B (421.16 ±104.52) compared to Group A (466.66 ±153.76), and these differences were statistically significant. Conclusions Higher levels of PEEP (10 and 5 cmH2O) during prone positioning in spine surgery improve arterial oxygenation, dynamic compliance, and hemodynamic stability while reducing intraoperative blood loss. These findings emphasize the importance of optimizing ventilatory support to enhance patient outcomes during prone-position surgeries.