Background This study aimed to investigate the correlation of sirtuin 2 (SIRT2) with acute ischemic stroke (AIS) risk, severity, inflammation, and prognosis. Methods A hundred and sixty-four first episode AIS patients and 164 age and gender matched non-AIS patients with high-stroke-risk factors (controls) were enrolled. Peripheral blood was collected and serum was separated for SIRT2 and pro-inflammatory cytokines detection by enzyme-linked immunosorbent assay. AIS patients were continually followed up to 36 months or death, then recurrence-free survival (RFS) and overall survival (OS) were calculated. Results Serum SIRT2 expression was increased in AIS patients compared to controls (p < 0.001), then receiver operative characteristic curve disclosed that the serum SIRT2 expression could differentiate AIS patients from controls with a good area under curve of 0.890 (95%CI: 0.854-0.926), a sensitivity of 78.7% and a specificity of 91.5% at the best cut-off point. Serum SIRT2 expression was positively correlated with National Institute of Health stroke scale score (p < 0.001), serum tumor necrosis factor-alpha (p < 0.001), interleukin (IL)-6 (p = 0.012) and IL-17 (p < 0.001) expressions in AIS patients. In addition, serum SIRT2 expression was elevated in recurrent/dead AIS patients compared to non-recurrent/dead AIS patients (p = 0.025), and was also increased in dead AIS patients compared to survivors (p = 0.006). Moreover, RFS (p = 0.029) and OS (p = 0.049) were both worse in AIS patients with SIRT2 high expression compared to AIS patients with SIRT2 low expression. Conclusion SIRT2 may serve as a marker for AIS risk and prognosis in clinical practice.