There is an immediate need for therapies related to coronavirus disease 2019 (COVID-19), especially candidate drugs that possess anti-inflammatory and immunomodulatory effects with low toxicity profiles. We hypothesized the application of pleiotropic tetracyclines as potential therapeutic candidates. Here, we present a retrospective multi-institutional cohort study evaluating ventilatory status in patients who had taken a tetracycline antibiotic within a year prior to diagnosis of acute respiratory distress syndrome (ARDS). The primary outcomes were the need for mechanical ventilation and duration of mechanical ventilation. The secondary outcome was the duration of intensive care unit (ICU) stay. Data was evaluated using logistic regression and treatment effects regression models. Minocycline or doxycycline treatment within a year prior to ARDS diagnosis was associated with a 75% reduced likelihood for mechanical ventilation during hospital stay. Furthermore, tetracycline antibiotic therapy corresponded to significant reductions in duration of mechanical ventilation and ICU stay in ARDS patients. These data suggest tetracyclines may provide prophylactic benefit in reducing ventilatory support for ARDS patients and support further evaluation in a randomized prospective trial.