The association between blood levels of protein Z (PZ) and risk of ischemic stroke remains poorly understood. We aimed to assess this potential relationship through a meta-analysis of case–control studies. PubMed, Scopus, Web of Science Core Collection, and the Cochrane Library were searched from April 1984 to April 2019. We selected case–control studies comparing PZ levels in adult patients with ischemic stroke and controls without ischemic stroke. Six case–control studies, with a total of 1,011 ischemic stroke patients and 1,128 controls, were included. Patients in the acute phase of ischemic stroke showed significantly higher levels of PZ compared with patients in the convalescent phase (standardized mean difference [SMD]: 0.289 mg/L; 95% confidence interval [CI]: 0.010, 0.569; p = 0.043). No significant differences in PZ levels were found between patients and controls in the acute phase (SMD: −0.059 mg/L; 95% CI: −0.570, 0.452; p = 0.821) or in the convalescent phase of ischemic stroke (SMD: −0.341 mg/L; 95% CI: −0.736, 0.055; p = 0.091). Subgroup analysis indicated that older patients (≥ 50 years old) had lower PZ levels than similarly aged controls. In contrast, when the study groups came from the United States and Australia or Europe no significant differences in PZ levels existed between patients and controls. No association between PZ and ischemic stroke was identified in this meta-analysis. The acute phase of ischemic stroke was associated with higher levels of PZ.