Objective: Administration of diuretics has been shown to assist fluid management and improve clinical outcomes in the critically ill post-shock resolution. Current guidelines have not yet included standardization or guidance for diuretic-based de-resuscitation in critically ill patients. This study aimed to evaluate the impact of a multi-disciplinary protocol for diuresis-guided de-resuscitation in the critically ill. Methods: This was a pre-post single-center pilot study within the medical intensive care unit (ICU) of a large academic medical center. Adult patients admitted to the Medical ICU receiving mechanical ventilation with either (1) clinical signs of volume overload via chest radiography or physical exam or (2) any cumulative fluid balance ≥ 0 mL since hospital admission were eligible for inclusion. Patients received diuresis per clinician discretion for a 2-year period (historical control) followed by a diuresis protocol for 1 year (intervention). Patients within the intervention group were matched in a 1:3 ratio with those from the historical cohort who met the study inclusion and exclusion criteria. Results: A total of 364 patients were included, 91 in the protocol group and 273 receiving standard care. Protocolized diuresis was associated with a significant decrease in 72-h post-shock cumulative fluid balance [median, IQR - 2257 (- 5676-920) mL vs 265 (- 2283-3025) mL; p < 0.0001]. In-hospital mortality in the intervention group was lower compared to the historical group (5.5% vs 16.1%; p = 0.008) and higher ICU-free days (p = 0.03). However, no statistically significant difference was found in ventilator-free days, and increased rates of hypernatremia and hypokalemia were demonstrated. Conclusions: This study showed that a protocol for diuresis for de-resuscitation can significantly improve 72-h post-shock fluid balance with potential benefit on clinical outcomes.