Background: Airway pressure release ventilation (APRV) is a potential alternative to conventional ventilation strategies in patients with moderate-to-severe acute respiratory distress syndrome (ARDS). This systematic review aims to evaluate the effects of APRV on oxygenation, lung compliance, mortality, and intensive care unit (ICU) outcomes in adult ARDS patients. Methods: A systematic search of PubMed, Scopus, and Web of Science was conducted in accordance with PRISMA guidelines to identify studies reporting clinical or physiological outcomes of APRV in moderate-to-severe ARDS. We include randomized controlled trials, observational studies, and feasibility trials comparing APRV to other ventilation modes. Data were extracted on patient demographics, intervention protocols, and outcomes. A qualitative synthesis was performed. Results: Seven studies with 528 patients were included, four randomized controlled trials, two observational studies, and one feasibility trial. APRV was associated with improved oxygenation indices (PaO₂/FiO₂), enhanced static lung compliance, and, in some studies, reduced mechanical ventilation duration and ICU stay. Zhou et al. show more ventilator-free days and reduced ICU mortality in APRV treated patients. Mortality outcomes were inconsistent in studies. While Ibarra-Estrada et al. found no significant mortality difference, others reported favorable trends. Studies reported improved physiological parameters with APRV, including better ventilation-perfusion matching and hemodynamic stability, with minimal adverse effects. Conclusions: APRV enhance oxygenation and lung mechanics in patients with moderate-to-severe ARDS and potentially reduce ICU stay. Its effect on mortality is inconclusive. Further high-quality, standardized trials are needed to assess its clinical benefits and establish implementation protocols.