The effectiveness of glucagon-like peptide-1 receptor agonists in facilitating weight loss among patients with diabetes is widely recognized. However, there are limited data available on the relative effectiveness and safety of once-weekly semaglutide versus once-daily liraglutide. We conducted a systematic review and meta-analysis of randomized controlled trials (RCTs) identified through a comprehensive search of the Cochrane Library, PubMed, and ScienceDirect databases from inception until July 2024. Statistical analysis was conducted using R version 4.4.1 with the "meta" package, employing a random effects model. Three RCTs with a total of 922 patients were included in our meta-analysis. The results indicated that OW semaglutide significantly reduced body weight (WMD: -4.55; 95% CI: -6.43, -2.67, p < 0.01), HbA1c (WMD: -0.46; 95% CI: -0.84, -0.08; p = 0.02), and fasting plasma glucose levels (WMD: -1.23; 95% CI: -1.51, -0.95; p < 0.01) in comparison to OD liraglutide. The risk of severe adverse effects (OR, 1.66; 95% CI, 0.53-5.16; p = 0.38) and gastrointestinal adverse effects (OR, 1.84; 95% CI, 0.82-4.14; p = 0.14) was comparable between both groups. Once-weekly semaglutide therapy results in a more pronounced loss in body weight, HbA1c, and fasting glucose levels compared to once-daily liraglutide.