Background Treatment of hypoxemic respiratory failure (HRF) and ARDS is complex. Standardized management of HRF and ARDS may improve adherence to evidence-informed practice and improve outcomes. Research Question What is the effect of standardized treatment compared with usual care on survival of patients with HRF and ARDS? Study Design and Methods MEDLINE, EMBASE, Cochrane, CINAHL, Scopus, and Web-of-Science were searched (inception to 2018). Included studies were randomized clinical trials or quasi-experimental studies that examined the effect of standardized treatment (care-protocol, care-pathway, or bundle) compared with usual treatment among mechanically ventilated adult patients admitted to an ICU with HRF or ARDS. Study characteristics, pathway components, and patient outcomes were abstracted independently by two reviewers. Results From 15,932 unique citations, 14 studies were included in the systematic review (three randomized clinical trials and 11 quasi-experimental studies). Twelve studies (including 5,767 patients) were included in the meta-analysis. Standardized management of HRF was associated with a 23% relative reduction in mortality (relative risk, 0.77; 95% CI, 0.65-0.91; I2, 70%; P = .002). In studies targeting patients with ARDS (n = 8), a 21% pooled mortality reduction was observed (relative risk, 0.79; 95% CI, 0.71-0.88; I2, 3.1%). Standardized management was associated with increased 28-day ventilator-free days (weighted mean difference, 3.48 days; 95% CI, 2.43-4.54 days; P Interpretation When compared with usual treatment, standardized treatment of patients with HRF and ARDS is associated with increased ventilator-free days, lower tidal volume ventilation, and lower mortality. ICUs should consider the use of standardized treatment to improve the processes and outcomes of care for patients with HRF and ARDS. Clinical Trial Registration PROSPERO; No.: CRD42019099921; URL: www.crd.york.ac.uk/prospero/