Background <p>Acute bacterial meningitis (ABM) is a life-threatening condition requiring prompt antibiotic administration to reduce mortality and neurological sequelae. The optimal timing of empiric antimicrobial therapy remains uncertain due to limited evidence.</p> Methods <p>We conducted a systematic review following Cochrane MECIR standards. The search was carried out on the 2nd of January 2024, including studies from 1946 to January 2024. We included randomized controlled trials and prospective cohort studies with comparator arms. Two reviewers independently screened studies, extracted data, and assessed risk of bias using the ROBINS-I tool. Meta-analyses were performed using RevMan Web, and certainty of evidence was evaluated with the GRADE approach.</p> Results <p>Three prospective cohort studies met the inclusion criteria. Very low-certainty evidence from 3 studies with 601 participants revealed an uncertain effect of early empiric antimicrobial treatment on all-cause mortality (RR 0.41, 95% CI 0.26–0.65; I²=44.9%). In addition, very low-certainty evidence from one study with 281 participants indicated an uncertain impact of pre-hospital admission i.e., early antibiotic therapy on development of neurological sequelae, including hearing loss (RR 2.98, 95% CI 1.09–8.13) and paresis (RR 2.21, 95% CI 0.93–5.25). This study also revealed an uncertain effect on CSF (RR 0.95, 95% CI 0.90–1.01) and blood culture positivity rates (RR 0.90, 95% CI 0.80–1.01). Very low-certainty evidence from another study with 148 participants revealed an uncertain impact of early antibiotic therapy (≤ 3&#xa0;h) on adverse events (RR 0.70, 95% CI 0.53–0.92).</p> Conclusion <p>The effect of early versus delayed empiric antimicrobial treatment for suspected ABM on mortality, neurological sequelae, and CSF and blood culture positivity rates is uncertain due to very low-certainty evidence. Further high-quality studies are needed to guide clinical practice.</p> Trial registration <p>PROSPERO registration, CRD42024531465.</p>