Background: Advanced and metastatic urothelial cancer (amUC) has a dismal prognosis. Enfortumab vedotin (EV), is a potent, novel antibody-drug conjugate (ADC) targeting Nectin-4. This study aimed to uncover the efficacy of EV in combination with Immune Checkpoint Inhibitors, specifically Pembrolizumab (P). Methods: This systematic review and meta-analysis followed the PRISMA guideline and the Cochrane handbook and has been registered on Prospero (CRD42024575788). Four databases were screened for clinical studies using EV and ICIs in patients with amUC. The retrieved records underwent risk of bias assessment using Cochrane RoB2 and ROBINS-I. Results: Four cohorts and seven RCTs were included, all displaying a low risk of bias. A total of 1,681 amUC patients with a history of receiving pembrolizumab were included in the analysis. The median overall survival (OS) was 11.76 months [95%CI (9.82–13.71); I2 = 49%]; OS12 of 78.59% [95%CI (74.91–82.26); I2 = 0%]. Compared to those previously treated with P, EV+P showed a superior overall response rate (ORR) (66.82% [95%CI (63.35–70.29); I2 = 0% vs. 44.78% [95%CI (41.04–48.53); I2 = 6%), progression-free survival (PFS) (6.35 months [95%CI (4.57–8.13); I2 = 77%] vs. 5.47 months [95%CI (5.17–5.77); I2 = 0%]) and exhibit lower mortality (HR 0.53; 95%CI [0.39–0.66]; I2 = 57%) and progression (HR 0.51; 95%CI [0.40–0.63]; I2 = 66%). Compared to those previously treated with P, EV+P regimen showed reduced mortality risk (HR 0.46; 95%CI [0.38–0.54]; I2 = 0% vs. 0.69; 95%CI [0.53–0.84]; I2 = 0%) and progression risk reduction (HR 0.44; 95%CI [0.38–0.51]; I2 = 0% vs. 0.69; 95%CI [0.53–0.84]; I2 = 0%). Associated adverse events (AE) showed no significant difference compared to chemotherapy (RR 0.94; [95%CI (0.78–1.10)]; I2 = 91%). Conclusion: EV showcased an excellent safety profile in amUC patients. Furthermore, this study uncovered synergistic effects of EV+P, prompting future cohorts and clinical trials regarding the concomitant use of both agents. © 2025 The Author(s). Published by Informa UK Limited, trading as Taylor & Francis Group.