Although interleukin-18 (IL-18) has been implicated in the pathophysiology of stroke, research findings concerning IL-18 level in stroke have been inconsistent. Thus, we performed a cross-sectional study in patients with first-episode ischemic stroke and then extracted relevant data from databases to validate our results. A total of 252 patients and 259 healthy subjects were recruited, and serum IL-18 level was evaluated in a cross-sectional study. Then, we extracted data and conducted a meta-analysis, including 2,928 patients and 3,739 controls to support our results. A 95% confidence interval for standardized mean difference (SMD) was calculated using a Z test. We found IL-18 was higher in stroke patients than in controls (2.39±0.25 vs. 2.25±0.28, F= 8.60, p= 0.004) and was negatively associated with the NIHSS scale (r=-0.14, p= 0.028). A subsequent meta-analysis confirmed that IL-18 level was higher in stroke patients than in controls (SMD= 2.14, 95% CI= 1.54∼ 2.73, P< 0.001). IL-18 level increased with the severity of the stroke (p< 0.01). These findings revealed increased IL-18 level contributed to the development and severity of ischemic stroke, suggesting the potential of this biomarker to become an important reference for the early monitoring of ischemic stroke.