This bicenter retrospective cohort study of 83 postoperative Crohn's disease patients with isolated anastomotic lesions (iAL) found that a neutrophil-to-lymphocyte ratio (NLR) > 2.45 is an independent risk factor for clinical recurrence (adjusted HR 2.88, 95% CI 1.39–6.00, p = 0.005). A simple risk score combining NLR and age at surgery (>45 years) further stratified patients, with those scoring 2 having a nearly 7-fold higher risk of clinical recurrence. NLR is a promising, non-invasive biomarker to guide personalized postoperative management in this heterogeneous patient subgroup.