Background and Objective: Hemorrhagic transformation (HT) is a major complication of acute ischemic stroke (AIS). Serum albumin is known for its neuroprotective effects and is a marker of improved AIS patient outcomes. However, it is not known whether there is a relationship between serum albumin and HT. Methods: AIS patients admitted to the Department of Neurology of West China Hospital from 2012 to 2016 were prospectively and consecutively enrolled. Baseline characteristics were collected. HT during hospitalization was diagnosed by brain imaging. Multivariate logistic regression analysis was performed to determine the relationship between serum albumin and HT. Confounding factors were identified by univariate analysis. Stratified logistic regression analysis was performed to identify effect modifiers. Results: A total of 1996 AIS patients were recruited, of whom 135 (6.8%) developed HT. Serum albumin negatively correlated with HT. Patients in the upper serum albumin tertile (42.6–54.1 g/L) had a 46% lower risk of HT than patients in the lower tertile (19.3–39.1 g/L) after adjustment for potential confounders (OR 0.54, 95% CI 0.29–0.99, p = 0.04). Risk of HT decreased stepwise with higher serum albumin tertile (p for trend = 0.04). There was a significant interaction between serum albumin and age (p = 0.02), with no significant correlation between serum albumin and HT in patients over 60 years of age. Conclusions: Higher serum albumin is associated with lower HT risk in a dose-dependent manner in AIS patients younger than 60 years.