Background: Sepsis is common, deadly, and a major challenge to treat. Quinolones added to beta-lactam antibiotics are currently recommended as a second-line empiric regimen in sepsis, but the evidence regarding their benefits and harms is unclear. Objective: To assess the benefits and harms of adding quinolones to standard care for sepsis. Data sources: We conducted a systematic review of randomized clinical trials with meta-analysis and Trial Sequential Analysis. We searched CENTRAL, MEDLINE, Embase, LILACS, SCI-Expanded, and BIOSIS. Study selection: Randomized clinical trials assessing the effects of adding any quinolone to standard care for children and adults with sepsis. Data extraction and synthesis: Two independent reviewers screened studies and extracted data. The certainty of the evidence was assessed by GRADE. Results: We included three trials randomizing 995 adults. All trials were at overall “high risk of bias.” All trials compared a quinolone (moxifloxacin, levofloxacin, or ciprofloxacin) and a beta-lactam antibiotic versus the same beta-lactam antibiotic. We found no evidence of an effect of adding quinolones to beta-lactam antibiotics when assessing all-cause mortality (RR 1.07, 95% CI 0.86 to 1.33; 2 trials; 915 participants; very low certainty of evidence) and serious adverse events (RR 1.00, 95% CI 0.67 to 1.50; 977 participants; two trials; very low certainty of evidence). No trials reported on quality of life. Conclusions: The effects of adding quinolones to beta-lactam antibiotics for the treatment of sepsis were unclear for all outcomes. Additional trial data are warranted to support the recommendation of empirical use of quinolones for sepsis.