Introduction: Psoriasis, a chronic inflammatory skin condition, affects 125 million worldwide. Current treatments provide symptomatic relief but face limitations. Guselkumab shows promise for moderate-to-severe psoriasis. Objective: We aimed to conduct a systematic review and meta-analysis exploring the safety and efficacy of guselkumab in moderate-to-severe psoriasis. Methods: We searched PubMed, EMBASE, and Cochrane Library for randomized controlled trials (RCTs) comparing guselkumab to placebo in moderate-to-severe psoriasis. Primary endpoints: Investigators’ Global Assessment (IGA) 0, Psoriasis Area and Severity Index (PASI) 90, and ≥1 adverse event (AE). Secondary endpoints: IGA 0/1, PASI75, PASI100, Dermatology Life Quality Index (DLQI), and ≥1 severe AE. RStudio was used for statistical analyses. Results: We included 1607 patients from 6 RCTs. Guselkumab significantly increased odds of IGA 0 (odds ratio (OR) OR: 73.87; 95%confidence interval (CI): 32.53-167.73; P<0.00001; I2=0.0%), and IGA 0/1 (OR: 54.84; 95% CI: 24.72–121.64; P<0.00001; I2=60.1%). Also, the OR of PASI75 (OR: 58.42; 95% CI: 23.03–148.17; P<0.001; I2=70.0%), PASI90 (OR: 46.47; 95% CI: 14.23–151.76; P<0.001; I2=71.7%), and PASI100 (OR: 59.27; 95% CI: 23.17–151.61; P<0.001; I2=0.0%) were higher with guselkumab. DLQI change was greater with guselkumab (MD: -8.46; 95% CI: -10.31 – -6.62; P<0.01; I²=77.8%). No significant difference in AEs and severe AEs between guselkumab and placebo (OR: 0.92; 95% CI: 0.68–1.24; P=0.58; I²=30.9%), (OR: 1.19; 95% CI: 0.54–2.64; P=0.66; I²=0.0%). Leave-one-out analysis identified PROTOSTAR as a source of heterogeneity. Subgroup analysis showed higher IGA 0 and PASI90 ORs in adults than in adolescents/children, with no dosage-based differences in PASI90 or AE. Conclusion: This meta-analysis suggests that guselkumab does significantly improve moderate-to-severe psoriasis, without a significant increase in AEs.