Background This study examined the effect of target transpulmonary driving pressure on mortality in patients with Acute Respiratory Distress Syndrome, assessing how varying levels of transpulmonary driving pressure influence clinical outcomes.Methods This retrospective study utilized data from the MIMIC-IV database to evaluate the relationship between transpulmonary driving pressure and mortality in Acute Respiratory Distress Syndrome. Associations between transpulmonary driving pressure levels and 28-day, ICU, and hospital mortality were analyzed. Propensity score matching was employed to balance covariates, while causal mediation analysis assessed whether peak airway pressure mediated the effect of transpulmonary driving pressure on mortality.Results Among 4721 patients with Acute Respiratory Distress Syndrome, 295 received transpulmonary driving pressure targeting. The optimal transpulmonary driving pressure threshold was identified as 12.5 cmH2O. Patients with transpulmonary driving pressure >12.5 cmH2O had significantly higher 28-day, ICU, and hospital mortality, particularly in those with moderate to severe Acute Respiratory Distress Syndrome (p < 0.05). After propensity score matching, targeting transpulmonary driving pressure was associated with lower ICU mortality (HR 0.676, 95% CI 0.511-0.894, p = 0.006). Phenotypic analysis showed that elevated transpulmonary driving pressure was linked to worse outcomes in Phenotype-I(High Mechanical Power with Moderate Lung Compliance) and Phenotype-II (High Spontaneous Breathing with Better Lung Compliance), but not in Phenotype-III (Low Tidal Volume with Reduced Lung Compliance). Mediation analysis revealed that 7.0% of the mortality risk associated with transpulmonary driving pressure >12.5 cmH2O was mediated through peak airway pressure.Conclusion Transpulmonary driving pressure exceeding 12.5 cmH2O is associated with higher mortality in Acute Respiratory Distress Syndrome patients, with peak airway pressure contributing to this effect.