Background: Mechanical ventilation is essential in managing critically ill adults, it contributes to ventilator induced lung injury (VILI). Driving pressure (ΔP), the difference between plateau pressure and PEEP, is a key parameter correlating with outcomes in mechanically ventilated patients. This systematic review evaluates the impact of driving pressure-guided ventilation (DPGV) strategies on clinical and physiological outcomes in adult patients. Methods: A systematic search was conducted in PubMed, Scopus, Web of Science, and Google Scholar for studies published between 2019 and 2025. Eligible studies included adult patients receiving mechanical ventilation with strategies targeting ΔP reduction. Outcomes of interest were mortality, postoperative pulmonary complications (PPCs), oxygenation, compliance, ventilator-free days, and duration of mechanical ventilation. Eight studies met inclusion criteria, including randomized controlled trials and cohort studies. Results: The included studies enrolled a total of 1,987 patients in ICU and surgical settings. Five studies how that ΔP-guided ventilation improved oxygenation and lung compliance. In ARDS patients, targeting ΔP ≤14–21 cm H₂O was associated with lower mortality, increased ventilator-free days, and successful weaning. In surgical patients, DPGV reduced the incidence of PPCs and postoperative atelectasis in most trials. The largest RCT found no significant difference in PPCs despite better intraoperative mechanics. Variability in measurement methods, thresholds, and patient populations limits comparability in studies. Conclusions: DPGV is associated with favorable physiological and selected clinical outcomes in mechanically ventilated adults. While results support its use in ARDS and surgical patients, larger trials with standardized protocols are needed to confirm its efficacy and optimize implementation.