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IntroductionCardiac arrest remains a common and devastating cause of death and disability worldwide. While targeted temperature management has become standard of care to improve functional neurologic outcome, few pharmacologic interventions have shown similar promise.Methods/analysisThis systematic review will focus on prospective human studies from 2015 to 2020 available in PubMed, Web of Science and EMBASE with a primary focus on impact on functional neurologic outcome. Prospective studies that include pharmacologic agents given during or after cardiac arrest will be included. Study selection will be in keeping with Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. If sufficient data involving a given agent are available, a meta-analysis will be conducted and compared with current evidence for therapies recommended in international practice guidelines.Ethics and disseminationFormal ethical approval will not be required as primary data will not be collected. The results will be disseminated through peer-reviewed publication, conference presentation and lay press.PROSPERO registration numberInternational Prospective Register for Systematic Reviews (CRD42021230216).