Abstract Aim: To systematically assess the quality and credibility of the correlations between H2RAs use with the risk of adverse outcomes. Methods: In accordance with PRISMA, Meta-analyses of observational studies and meta-analyses of randomized controlled trials (RCTs) were included through searching 4 major databases from inception to 30 April 2022. AMSTAR 2 and GRADE were used to assess quality and certainty of evidence. Results: Forty-six individual meta-analyses were identified, including 30 meta-analyses of observation researches with 32 unique outcomes and 19 meta-analyses of randomized controlled trails with 3 unique outcomes for comparing H2RAs versus non-H2RAs group. We confirmed significant associations of H2RAs use with pneumonia (OR, 1.31; 95% CI, 1.04-1.64), peritonitis (OR, 2.16; 95% CI, 1.65-2.84), necrotizing enterocolitis (OR, 1.80; 95% CI, 1.21-2.67), C difficile infection (OR, 1.25; 95% CI, 1.05-1.49), asthma(OR, 1.48; 95% CI 1.36-1.62), liver cancer(OR, 1.41; 95% CI, 1.36-1.46), gastric cancer(OR, 1.41; 95% CI, 1.21-1.64) and hip fracture diseases(OR, 1.20; 95% CI, 1.13-1.27). No associations for colorectal cancer, melanoma, kidney cancer, lung cancer, common reproductive system cancer, renal, neurological, and cardiovascular system diseases were observed. Conclusions: We found a variety of evidence for the associations between H2RAs and adverse outcomes, which would give clinicians more positive guidance on prescription of H2RAs in clinical practice.