ObjectiveAutophagy‐related 5 (ATG5) facilitates the pathologic process of acute ischemic stroke (AIS) via multiple ways. This study aimed to identify the association of serum ATG5 with clinical outcomes in AIS patients.MethodsSerum ATG5 from 280 AIS patients were detected at admission, Day (D)1, D3, D7, D30, and D90 after admission by enzyme‐linked immunosorbent assay. The median (interquartile range) follow‐up was 21.1 (5.9–43.9) months. Another 50 healthy controls (HCs) were also enrolled for serum ATG5 determination.ResultsATG5 was elevated (p < 0.001) (vs. HCs), and positively correlated with hyperlipidemia (p = 0.016), and the national institutes of health stroke scale score (p = 0.001) in AIS patients. Interestingly, ATG5 was increased from admission to D1, but gradually decreased until D90 (p < 0.001). Besides, 85 (30.4%) and 195 (69.6%) AIS patients were assessed as modified Rankin Scale (mRS) >2 and mRS ≤2 at D90, respectively. ATG5 at admission, D1, D3, D30, and D90 was elevated in AIS patients with mRS >2 versus those with mRS ≤2 (all p < 0.050). ATG5 at admission, D1, D3, D7, D30, or D90 was elevated in relapsed (vs. non‐relapsed) or died (vs. survived) AIS patients (all p < 0.050). Recurrence‐free survival was shortened in AIS patients with high (≥52.0 ng/mL) ATG5 versus those with low (<52.0 ng/mL) ATG5 at admission, D3, D7, and D30 (all p < 0.050); overall survival was shorter in AIS patients with high (vs. low) ATG5 at D7 and D30 (both p < 0.050).InterpretationSerum ATG5 elevates at first, thereafter gradually declines, whose elevation associates with neurological dysfunction, recurrence, and death risk in AIS patients.