Background <p>Despite the increasing clinical use of glucagon-like peptide-1 receptor agonists (GLP-1 RAs), head-to-head evidence across these agents remains limited. This systematic review and network meta-analysis (NMA) will assess the comparative efficacy and safety of GLP-1 RAs and novel co-agonists for weight loss among adults without diabetes.</p> Methods <p>We will systematically search the PubMed, Ovid, and Cochrane CENTRAL databases to identify randomized controlled trials (RCTs) comparing a GLP-1 RA/co-agonist to placebo or another GLP-1 RA/co-agonist. We will restrict inclusion to RCTs in adults with overweight or obesity; those including participants with diabetes, specific comorbidities or diseases, or history of bariatric surgery will be excluded. The primary outcome will be weight loss, expressed as relative change from baseline, assessed at 6&#xa0;months (± 4&#xa0;weeks) and 1–1.5&#xa0;years (± 4&#xa0;weeks). Secondary outcomes will include absolute body weight change, total adverse events, gastrointestinal adverse events, serious adverse events, and death. Pairwise meta-analyses and frequentist NMAs will be conducted using a random-effects model. Treatment rankings for efficacy and safety outcomes will be generated using the surface under the cumulative ranking curve. The validity of the results and the assumptions underlying the analyses will be evaluated using a local and global approach. Study-level quality will be assessed using the Cochrane Risk of Bias (RoB) 2 tool and overall network quality will be assessed using the RoB-NMA tool.</p> Discussion <p>We aim to provide an up-to-date synthesis of RCTs assessing the weight loss effects of GLP-1 RAs and co-agonists among adults without diabetes to support future clinical decision-making, guideline development, and policy decisions.</p> Systematic review registration <p>PROSPERO CRD420251009368</p>