Background/Objectives: Managing ventilatory strategies in patients with obesity under general anesthesia presents significant challenges due to obesity-related pathophysiological changes. Inverse ratio ventilation (IRV) has emerged as a potential strategy to optimize respiratory mechanics during laparoscopic surgery in this population. The primary outcomes were changes in respiratory mechanics, including peak inspiratory pressure (P_Peak), plateau pressure (P_Plat), mean airway pressure (P_Mean), and dynamic compliance (C_Dyn). Secondary outcomes included gas exchange parameters, hemodynamic measures, inflammatory cytokines, and postoperative complications. Methods: A systematic review and meta-analysis were conducted, searching PubMed, Scopus, EMBASE, and PMC Central. Only English-language randomized controlled trials (RCTs) evaluating the impact of IRV in adult surgical patients with obesity were included. The quality and certainty of evidence were assessed using the Risk of Bias 2 (RoB 2) tool and the Grades of Recommendation, Assessment, Development, and Evaluation (GRADE) framework, respectively. Results: Three RCTs including 172 patients met the inclusion criteria. Compared to conventional ventilation without prolonged inspiratory time or IRV, IRV significantly reduced P_Peak (MD [95%CI]: −3.15 [−3.88; −2.42] cmH₂O, p < 0.001) and P_Plat (MD [95%CI]: −3.13 [−3.80; −2.47] cmH₂O, p < 0.001) while increasing P_Mean (MD [95%CI]: 4.17 [3.11; 5.24] cmH₂O, p < 0.001) and C_Dyn (MD [95%CI]: 2.64 [0.95; 4.22] mL/cmH₂O, p = 0.002) during laparoscopy, without significantly affecting gas exchange. IRV significantly reduced mean arterial pressure (MD [95%CI]: −2.93 [−3.95; −1.91] mmHg, p < 0.001) and TNF-α levels (MD [95%CI]: −9.65 [−17.89; −1.40] pg/mL, p = 0.021). Conclusions: IRV optimizes intraoperative respiratory mechanics but has no significant impact on postoperative outcomes, necessitating further research to determine its clinical role.