Fecal lactoferrin (FL) is associated with disease activity and relapse in ulcerative colitis. However, whether FL could early predict long‐term outcomes in ulcerative colitis is poorly understood. This post‐hoc analysis included participants who received biologics and had available data of FL concentration at week 4 from the UNIFI and PURSUIT trials (n= 1063). Therapeutic outcomes, including clinical remission, endoscopic improvement and remission, and histological improvement and remission, were evaluated at the end of maintenance therapy. The incidence of colectomy was observed from week 0 to maximum week 228 in the PURSUIT trial (n= 667). Multivariate logistic and Cox proportional‐hazard regression were conducted to evaluate the associations between FL and therapeutic outcomes and colectomy, respectively. A high FL level at week 4 was associated with poor long‐term clinical, endoscopic and histologic outcomes. FL >84.5 μg/mL predicted a low likelihood of clinical (OR [95% CI]: 0.43 [0.32, 0.57]; p< 0.001), endoscopic (OR [95% CI]: 0.40 [0.29, 0.56]; p< 0.001), and histological (OR [95% CI]: 0.27 [0.14, 0.53]; p< 0.001) remission. Moreover, week‐4 FL could add prognostic value to fecal calprotectin and clinical and endoscopic scores for informing long‐term therapeutic outcomes. For the risk of colectomy, patients with week‐4 FL <20.1 and ≥20.1 µg/mL had an incidence rate of 1.10% and 6.39%, respectively. Patients with FL ≥20.1 µg/mL had a 995% higher risk of colectomy (HR [95% CI], 10.95 [1.45, 82.74]). FL could be a promising prognostic biomarker for long‐term therapeutic outcomes and risk of colectomy in patient of ulcerative colitis.