Background Diabetes mellitus is a major risk factor for ischemic stroke. Rising hemoglobin A _1c (HbA _1c ) levels are associated with microvascular diabetes mellitus complication development; however, this relationship has not been established for stroke risk, a macrovascular complication. Methods and Results We conducted a systematic review and meta‐analysis of observational cohort and nested case‐control cohort studies assessing the association between rising HbA _1c 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 HbA _1c (<5.7%), diabetes mellitus range HbA _1c (≥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 HbA _1c (5.7–6.5%) was not (average HR [95% confidence interval], 1.19 [0.87, 1.62]). For every 1% HbA _1c 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% HbA _1c 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. Conclusions A rising HbA _1c 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 HbA _1c glycemic control targets may be required for optimal ischemic stroke prevention.