Background: New approaches involving immune checkpoint inhibitors (ICIs) and antibody-drug conjugates prolong overall survival (OS) in patients with metastatic urothelial carcinoma (mUC). However, the access to such systemic therapy in clinical practice is suboptimal, and whether these agents improve OS in patients with mUC over time remains unclear. In the present study, we investigated the OS trend from the initiation of first-line therapy with these agents to identify changes due to the medication and time of treatment initiation. Methods: We retrospectively evaluated 195 patients who received platinum-based chemotherapy as a first line treatment. The patients were treated with chemotherapy, pembrolizumab, avelumab, or enfortumab vedotin (EV) sequentially and were divided into the following three groups: chemotherapy period (April 2009–June 2017; P1), pembrolizumab period (July 2017–December 2020; P2), and avelumab and EV period (January 2021–August 2022; P3) based on the regulatory approval. Data cutoff was set at July 31, 2023. Results: OS was prolonged over time by the new therapeutic agents, and median OS was 11, 25, not reached, and 35.5 months for patients who were treated with chemotherapy, pembrolizumab, avelumab, or EV, respectively. However, median OS was 14, 18 months, and not reached in P1, P2 and P3, respectively. Analysis by periods showed that OS was significantly longer in P2 than in P1 (HR = 0.62, 95% CI: 0.43–0.89, P = 0.009) and in P3 than in P1 (HR = 0.47, 95% CI: 0.28–0.78, P = 0.015). No difference was observed in OS between P2 and P3 (HR = 0.66, 95% CI: 0.36–1.20, P = 0.21). Overall, the proportion of patients who received ICIs increased over time, as indicated by the fact that 77 and 95 patients received ICIs (pembrolizumab or avelumab) in P2 and P3, respectively. However, the prevalence of the treatment with EV was only 24%, and 43% of patients who received pembrolizumab received best supportive care. Conclusions: This study showed an improvement in OS over time in patients with mUC in real-world practice and may indicate the importance of not missing the appropriate opportunity to receive sequential treatments.