Background <p>Vonoprazan (VPZ), a potassium-competitive acid blocker, has emerged as an alternative to traditional proton-pump inhibitors like Lansoprazole (LPZ) for the treatment of erosive esophagitis (EE). Vonoprazan provides stronger acid suppression compared to PPIs; however, evidence regarding its effectiveness and safety in treating EE remains limited. We conducted a systematic review and meta-analysis to evaluate the comparative effectiveness and safety of VPZ versus LPZ in the healing and maintenance phases of EE.</p> Methods <p>A comprehensive literature search was conducted across PubMed, Embase and Cochrane Library to identify eligible randomized controlled trials (RCTs) published till 12 December 2024 that evaluated efficacy and safety of VPZ and LPZ in patients with EE. Outcomes included endoscopic healing rates, recurrence rates, and treatment-emergent adverse events (TEAEs). Pairwise meta-analyses and network meta-analyses (NMA) were performed using Review Manager 5.4.1 and Bayesian models.</p> Results <p>This meta-analysis included 7 RCTs with 4,903 patients. In the healing phase, VPZ showed significantly higher endoscopic healing rates than LPZ at Week 2 (RR: 1.09; 95% CI: 1.04–1.13; <i>p</i> &lt; 0.0001, <i>I</i>² = 0%) and among patients with severe EE (LA classification C/D) at both Week 2 (RR: 1.26; 95% CI: 1.15–1.38; <i>p</i> &lt; 0.00001, <i>I</i>² = 0%) and Week 8 (RR: 1.13; 95% CI: 1.03–1.24; p = 0.007, <i>I</i>² = 67%). No significant differences were observed in TEAEs, severe adverse events, or treatment discontinuation. In the maintenance phase, VPZ 20&#xa0;mg reduced recurrence rates compared to LPZ 15&#xa0;mg (RR: 0.41; 95% CI: 0.17–0.85) without differences in TEAEs.</p> Conclusions <p>VPZ demonstrates greater efficacy in healing and maintaining remission in EE, particularly in severe cases, with a safety profile comparable to LPZ. These findings support VPZ as an effective alternative to PPIs. However, long-term studies are warranted.</p>