The study evaluated the efficacy and safety of advanced combination therapy with upadacitinib (ACT-U, upadacitinib plus biologics) in patients with refractory Crohn's disease after failure of at least one biologic. This was a single-center, retrospective observational study at Yancheng No.1 People’s Hospital, China, with patients with a median age of 27.5 years (IQR 23.3–32.0) and a median disease duration of 4.0 years (3.0–6.0). Treatment lasted an average of 14.5 weeks (11.0–18.0). The median HBI score decreased from 7 (6–8) to 2 (2–4) (p < 0.01); all patients achieved clinical response (95% CI: 85.8–100%) and 91.7% remission (95% CI: 73.0–99.0%). Median SESCD decreased from 15 (13–17) to 1 (0–2) (p < 0.01); all patients had endoscopic improvement (95% CI: 85.8–100%), 83.3% remission (95% CI: 62.6–95.3%), and 45.8% mucosal healing (95% CI: 25.6–67.2%). Mild adverse events occurred in 23.1% of patients (95% CI: 9.0–43.6%; acne, gastrointestinal disturbances, mild infections), including one case of transient semen discoloration; no serious adverse events or surgical procedures were reported. The results are consistent with the goals of STRIDE-II, but the study emphasizes the need for prospective research to verify long-term effects.