Sepsis is a common life-threatening, acute and severe disease with high morbidity and mortality, which seriously endangers patient health. Shengmai injection (SMI) is typically used as an alternative treatment for sepsis patients. This investigation aimed at designing a comprehensive recollection and meta-analytical exercise for evaluating efficacy and safety-profile for employing SMI against sepsis.Multiple research literature repositories, both localized and global, were examined for randomized controlled trials of sepsis treated by SMI - from repository inception to December 2021 as a timeframe. Primary outcome measures contained 28-day all-cause mortality, while secondary outcome measures consisted of Sequential Organ Failure Assessment scorings, acute Physiology and Chronic Health Evaluation II scorings, ICU-based hospitalization length, mechanical ventilation timespan, ICU mortality rate, and adverse effects/events. RevMan V.5.3 was employed for data analyses. Two reviewers evaluated bias risks/investigation quality through Cochrane Collaboration risk of bias tool / Grades of Recommendations Assessment Development and Evaluation, separately.Such a comprehensive reviewing protocol review protocol systematically and objectively analyzes the effectiveness and safety-profile of SMI for therapy against sepsis, together with providing scientific grounds for clinic-based employment for SMI.CRD42021245247.Copyright © 2022 the Author(s). Published by Wolters Kluwer Health, Inc.