Ulcerative colitis (UC) is a serious health problem that requires a constant need to identify new effective drugs. The aim of this study was to assess the efficacy and safety of mirikizumab compared with other biologic drugs approved for the treatment of moderately to severely active UC. This systematic review with frequentist network meta-analysis (NMA) included randomized controlled trials (RCTs) that evaluated the use of adalimumab, golimumab, infliximab, mirikizumab, vedolizumab, and ustekinumab compared with placebo or with another approved biologic drug. The NMA was conducted using the netmeta R software package. The P score was used to determine the treatment ranking. A total of 14 RCTs were included in the analysis. No significant differences were observed in the incidence of clinical response and remission between mirikizumab and other drugs. Mirikizumab was superior to placebo for clinical response (induction: odds ratio [OR] = 2.38; 95% confidence interval [CI]: 1.63-3.48; maintenance: OR = 3.31, 95% CI: 1.59-6.89) and remission (induction: OR = 2.09, 95% CI: 1.20-3.63; maintenance: OR = 2.96; 95% CI: 1.62-5.40). The probability plot indicated that infliximab might be the most effective option in terms of both clinical response and remission (P score, 0.8971 and 0.8814, respectively) in induction phase. No significant differences were noted between the studied drugs in any adverse events (AEs), serious AEs (SAEs) and infections for the induction phase, and in any AEs, infections and serious infections for the maintenance phase. The drugs differed in terms of discontinuation due to AEs (induction and maintenance phases) as well as SAEs and serious infections (maintenance phase). Mirikizumab did not differ from other biologics in terms of clinical response and remission for both induction and maintenance phases in patients with UC. Mirikizumab during the induction phases achieved rank 3 for clinical response and rank 5 for clinical remission. Therefore, it represents a valuable treatment option. The lack of significant differences in the risk of AEs and SAEs suggests that mirikizumab has a similar safety profile to the other drugs.