Background: Mechanical ventilation brings the risk of ventilator-induced lung injury, which can lead to pulmonary fibrosis and prolonged mechanical ventilation. Methods: A retrospective analysis of patients with acute respiratory distress syndrome (ARDS) who received open lung biopsy between March 2006 and December 2019. Results: A total of 68 ARDS patients receiving open lung biopsy with diffuse alveolar damage (DAD; the hallmark pathology of ARDS) were analyzed and stratified into non-fibrosis (n = 56) and fibrosis groups (n = 12). The duration of ventilator usage and time spent in the intensive care unit and hospital stay were all significantly higher in the fibrosis group. Hospital mortality was higher in the fibrosis than in the non-fibrosis group (67% vs. 57%, p = 0.748). A multivariable logistic regression model demonstrated that mechanical power at ARDS diagnosis and ARDS duration before biopsy were independently associated with histological fibrosis at open lung biopsy (odds ratio 1.493 (95% CI 1.014–2.200), p = 0.042; odds ratio 1.160 (95% CI 1.052–1.278), p = 0.003, respectively). Conclusions: Our findings indicate that prompt action aimed at staving off injurious mechanical stretching of lung parenchyma and subsequent progression to fibrosis may have a positive effect on clinical outcomes.