Objective: To investigate the effects of prophylactic use of stimulant laxatives and/or docusate on the clinical outcomes in critically ill patients who required mechanical ventilation (MV). Methods: A single-center, retrospective, cohort study was conducted. Patients who received MV in the first 24 h after intensive care unit (ICU) admission were enrolled and divided into four groups: non-laxative, stimulant laxatives, docusate, and stimulant laxatives–docusate combination. The primary outcome was in-hospital mortality. The major secondary outcomes included ICU-free days and ventilator-free days at 28 days; the other outcomes were ventilation-associated pneumonia (VAP), enterobacterial infection, diarrhea, and electrolyte disturbances. Inverse probability treatment weighting (IPTW) was used to adjust for confounders. Results: A total of 2129 patients were included in this study, 263 of whom received stimulant laxatives, 253 received docusate, 368 received a combination, and 1245 did not receive any laxative. The prophylactic use of docusate was associated with a decreased risk of in-hospital mortality (OR: 0.59, 95% CI 0.42 to 0.83, p = 0.002) and VAP (OR: 0.62, 95% CI 0.47 to 0.81, p = 0.001). It was also associated with an increase in ICU-free days at 28 days (β: 0.89, 95% CI 0.83 to 0.95, p < 0.001). Importantly, laxatives prophylaxis was not associated with increased risks of diarrhea, electrolyte disturbances, and enterobacterial infections. Conclusions: Prophylactic use of docusate may improve certain prognoses and does not demonstrate any adverse events. However, further research is necessary to determine the optimal regimen and dosage of prophylactic laxatives in this specific population.