BackgroundDiabetes mellitus is a major risk factor for ischemic stroke. Rising hemoglobin A1c (HbA1c) levels are associated with microvascular diabetes mellitus complication development; however, this relationship has not been established for stroke risk, a macrovascular complication.Methods and ResultsWe conducted a systematic review and meta‐analysis of observational cohort and nested case‐control cohort studies assessing the association between rising HbA1c levels and stroke risk in adults (≥18 years old) with and without type 1 or type 2 diabetes mellitus. Random‐effects model meta‐analyses were used to calculate pooled adjusted hazard ratios (HRs) and their precision. The systematic review yielded 36 articles, of which 29 articles (comprising n=532 779 participants) were included in our meta‐analysis. Compared to non–diabetes mellitus range HbA1c (<5.7%), diabetes mellitus range HbA1c (≥6.5%) was associated with an increased risk of first‐ever stroke with average HR (95% confidence interval) of 2.15 (1.76, 2.63), whereas pre–diabetes mellitus range HbA1c (5.7–6.5%) was not (average HR [95% confidence interval], 1.19 [0.87, 1.62]). For every 1% HbA1c increment (or equivalent), the average HR (95% confidence interval) for first‐ever stroke was 1.12 (0.91, 1.39) in non–diabetes mellitus cohorts and 1.17 (1.09, 1.25) in diabetes mellitus cohorts. For every 1% HbA1c increment, both non–diabetes mellitus and diabetes mellitus cohorts had a higher associated risk of first‐ever ischemic stroke with average HR (95% confidence interval) of 1.49 (1.32, 1.69) and 1.24 (1.11, 1.39), respectively.ConclusionsA rising HbA1c level is associated with increased first‐ever stroke risk in cohorts with a diabetes mellitus diagnosis and increased risk of first‐ever ischemic stroke in non–diabetes mellitus cohorts. These findings suggest that more intensive HbA1c glycemic control targets may be required for optimal ischemic stroke prevention.