Uric acid (UA) is an antioxidant with neuroprotective effects in experimental stroke models. Whether serum UA plays a role in hemorrhagic transformation (HT) remains unclear. We aimed to explore the association between serum UA and HT in patients with acute ischemic stroke (AIS). AIS patients within 7 days after stroke onset were consecutively enrolled between January 2016 and October 2017. Patients were categorized into three groups according to serum UA tertiles by sex. HT was detected by follow-up CT or MRI within 7 days after admission. The multivariate logistic analysis was performed to assess the association of serum UA with HT. We included 1230 patients (mean age 64.1 years, 63.5% males) and 133 (10.8%) patients experienced HT. After adjusting confounders, patients in the second and third UA tertiles showed a significant decrease in HT compared with those in the lowest tertile (OR 0.432, 95% CI 0.266-0.702; OR 0.033, 95% CI 0.013-0.086, respectively). Similar results were observed for sex-based subgroups. Males with higher UA had lower risk of HT compared with the lowest UA tertile (OR 0.332, 95% CI 0.170-0.651; OR 0.008, 95% CI 0.001-0.070, respectively). In females, the highest UA tertile was inversely associated with HT (OR 0.148, 95% CI 0.058-0.376). Multiple-adjusted spline regression analyses further confirmed the dose-response relationship between UA levels and HT. Higher serum UA is independently associated with lower HT following stroke. More studies are needed to elucidate the potential neuroprotective mechanism of serum UA and its link to HT.