Olokizumab (OKZ) is a novel IL-6 inhibitor that directly targets IL-6 rather than its receptor. We aim to evaluate the efficacy and safety of OKZ for patients with rheumatoid arthritis (RA) and to investigate the optimal treatment regimen. A systematic review, pairwise, and network meta-analysis synthesizing randomized controlled trials (RCTs) from WOS, CENTRAL, SCOPUS, EMBASE, and PubMed until August 31, 2022. We used the risk ratio (RR) and mean difference (MD) for dichotomous and continuous outcomes, respectively, presented with the corresponding 95% confidence interval (CI). We registered our protocol in PROSPERO with ID:CRD42022358082. Five RCTs with 2277 patients were included. OKZ significantly improved the American College of Rheumatology criteria (ACR) 20 (RR: 1.97 with 95% CI [1.49, 2.58],P= 0.00001), ACR50 (RR: 3.83 with 95% CI [2.13, 6.87],P= 0.00001), ACR70 (RR: 3.83 with 95% CI [2.13, 6.87],P= 0.00001), disease activity score 28 based on C-reactive protein (DAS28-CRP) (RR: 3.91 with 95% CI [2.65, 5.79],P= 0.00001), clinical disease activity index (CDAI) (RR: 2.80 with 95% CI [1.43, 5.48],P= 0.003), and health assessment questionnaire disability index (HAQ-DI) (MD: − 0.28 with 95% CI [− 0.38, − 0.18],P= 0.00001) after 12 weeks, compared to placebo. However, OKZ was also associated with a higher incidence of any adverse events (AEs) (RR: 1.15 with 95% CI [1.06, 1.25], P = 0.0005) and AEs leading to drug discontinuation (RR: 1.86 with 95% CI [1.05, 3.29], P = 0.03). OKZ is effective and with acceptable safety profile when administrated with methotrexate in patients with RA not adequately controlled by tumor necrosis factor inhibitors; however, more large-scale RCTs are still required to investigate the optimal dosing, long-term effects, and comparative efficacy versus established biological DMARDs.Key Points•OKZ is effective especially with methotrexate in RA patients.Supplementary InformationThe online version contains supplementary material available at 10.1007/s10067-023-06519-6.