Objective <p>The therapeutic landscape for advanced or metastatic renal cell carcinoma (mRCC) has evolved to incorporate both anti‑VEGF/VEGFR monotherapy and its combination with immune checkpoint inhibitors (ICIs). Direct head‑to‑head comparisons among all available regimens are lacking. This network meta‑analysis (NMA) aimed to comprehensively evaluate their relative efficacy and safety to better inform clinical decision‑making.</p> Methods <p>We conducted a Bayesian NMA of randomized controlled trials (RCTs) retrieved from PubMed, Embase, Web of Science, the Cochrane Library and ClinicalTrials.gov up to May 2025. Efficacy outcomes included overall survival (OS), progression-free survival (PFS), and the objective response rate (ORR). Safety outcomes included grade ≥ 3 adverse events (AEs), treatment discontinuation due to AEs, and specific AEs.Treatments were ranked according to the surface under the cumulative ranking curve (SUCRA), which indicates the probability of a regimen being among the best options.</p> Results <p>A total of 24 randomized controlled trials (RCTs) involving 10,271 patients with advanced or metastatic renal cell carcinoma were included, covering 17 therapeutic approaches. According to SUCRA rankings, toripalimab plus axitinib had the highest probability of ranking first for OS benefit (SUCRA = 0.849) and was significantly superior to tivozanib (HR = 2.14, 95% CI: 1.01–4.64). but not over other comparators.While lenvatinib plus pembrolizumab had the highest probability of ranking first for PFS (SUCRA = 0.939) and showed significant superiority over most monotherapies (e.g., HR = 0.47, 95% CI: 0.34–0.65 vs. sunitinib), its comparative effectiveness was not statistically different from either cabozantinib monotherapy or other ICI-based combinations. Bembelstobart plus anlotinib achieved the highest ORR (SUCRA = 0.972). Regarding grade ≥ 3 AEs, anlotinib monotherapy had the highest probability of ranking as the most favorable option (SUCRA = 0.904), whereas lenvatinib plus pembrolizumab had the highest probability of ranking as the least favorable option (SUCRA = 0.107). Regarding specific adverse events, tivozanib and the 2-week-on/1-week-off sunitinib regimen were ranked as the most favorable options for hand-foot syndrome and fatigue, respectively. For treatment discontinuation due to AEs, bevacizumab plus atezolizumab had the highest probability of being the most favorable option. Subgroup analyses supported the favorable profile of combination therapy in intermediate‑/high‑risk and Asian populations.</p> Conclusion <p>Based on SUCRA rankings, ICI‑based combinations showed more favorable efficacy probabilities than VEGF/VEGFR‑targeted monotherapy. Toripalimab plus axitinib ranked among the best options for overall survival (OS), particularly in Asian and intermediate‑/poor‑risk patients. Although lenvatinib plus pembrolizumab ranked high for progression‑free survival (PFS), its higher probability of severe toxicity requires careful management. Nivolumab plus cabozantinib and bembelstobart plus anlotinib also demonstrated favorable efficacy rankings. For favorable‑risk patients, pazopanib presented a balanced efficacy‑risk profile, with lenvatinib plus pembrolizumab as a potential alternative.</p>