<b><i>Introduction:</i></b> In patients with acute ischemic stroke, the location and volume of an irreversible infarct core determine prognosis and treatment. We aimed to determine if automated CT perfusion (CTP) is non-inferior to diffusion-weighted imaging (DWI) or fluid-attenuated inversion recovery (FLAIR) in predicting the acute infarct core. <b><i>Methods:</i></b> In this systematic review and meta-analysis, we searched MEDLINE and EMBASE from 1960 to December 2020. Five outcome measures were examined: volumetric difference, volumetric correlation, sensitivity and specificity at the patient level, Dice coefficient, and sensitivity and specificity at the voxel level. A random-effects meta-analysis was performed for volumetric difference and correlation. <b><i>Results:</i></b> From 3,986 studies retrieved, 48 studies met our inclusion criteria with 46 studies on anterior circulation, one study on posterior circulation, and one study on lacunar infarct strokes. In anterior circulation stroke, there were no significant mean volumetric differences between CTP and acute DWI (cerebral blood flow [CBF] 0.52 mL, 95% CI [−0.07, 1.11], <i>I</i><sup>2</sup> 0.0%; relative CBF [rCBF] 3.01 mL, 95% CI [−0.46, 6.48], <i>I</i><sup>2</sup> 82.6%; relative cerebral blood volume [rCBV] −12.84 mL, 95% CI [−38.56, 12.88], <i>I</i><sup>2</sup> 96.2%) and between CTP and delayed DWI or FLAIR (rCBF −1.29 mL, 95% CI [−6.49, 3.92], <i>I</i><sup>2</sup> 91.8%; rCBV −5.80 mL, 95% CI [−16.20, 4.60], <i>I</i><sup>2</sup> 84.2%). Mean correlation between CTP and acute DWI was 0.90 (95% CI [0.80, 0.95], <i>I</i><sup>2</sup> 60.0%) for rCBF and 0.84 (95% CI [0.58, 0.94], <i>I</i><sup>2</sup> 93.5%) for rCBV. Mean correlation between CTP and delayed DWI or FLAIR was 0.74 (95% CI [0.57, 0.85], <i>I</i><sup>2</sup> 94.6%) for rCBF and 0.90 (95% CI [0.69, 0.97], <i>I</i><sup>2</sup> 93.1%) for rCBV. Sensitivity and specificity at the patient level were reported by three studies and Dice coefficient by four studies. Statistical analysis could not be performed for sensitivity and specificity at the voxel level. Limited evidence was available for posterior circulation or lacunar infarct strokes. <b><i>Conclusion:</i></b> Due to significant heterogeneity and insufficient high-quality studies reporting each outcome, there is insufficient evidence to reliably determine the accuracy of CTP prediction of the infarct core compared to DWI or FLAIR.