Background and Purpose Multiphase computed tomographic angiography (mCTA) provides time variant images of pial vasculature supplying brain in patients with acute ischemic stroke (AIS). To develop a machine learning (ML) technique to predict tissue perfusion and infarction from mCTA source images.Methods 284 patients with AIS were included from the Precise and Rapid assessment of collaterals using multi-phase CTA in the triage of patients with acute ischemic stroke for Intra-artery Therapy (Prove-IT) study. All patients had non-contrast computed tomography, mCTA, and computed tomographic perfusion (CTP) at baseline and follow-up magnetic resonance imaging/non-contrast-enhanced computed tomography. Of the 284 patient images, 140 patient images were randomly selected to train and validate three ML models to predict a pre-defined Tmax thresholded perfusion abnormality, core and penumbra on CTP. The remaining 144 patient images were used to test the ML models. The predicted perfusion, core and penumbra lesions from ML models were compared to CTP perfusion lesion and to follow-up infarct using Bland-Altman plots, concordance correlation coefficient (CCC), intra-class correlation coefficient (ICC), and Dice similarity coefficient.Results Mean difference between the mCTA predicted perfusion volume and CTP perfusion volume was 4.6 mL (limit of agreement [LoA], –53 to 62.1 mL; <i>P</i>=0.56; CCC 0.63 [95% confidence interval [CI], 0.53 to 0.71; <i>P</i><0.01], ICC 0.68 [95% CI, 0.58 to 0.78; <i>P</i><0.001]). Mean difference between the mCTA predicted infarct and follow-up infarct in the 100 patients with acute reperfusion (modified thrombolysis in cerebral infarction [mTICI] 2b/2c/3) was 21.7 mL, while it was 3.4 mL in the 44 patients not achieving reperfusion (mTICI 0/1). Amongst reperfused subjects, CCC was 0.4 (95% CI, 0.15 to 0.55; <i>P</i><0.01) and ICC was 0.42 (95% CI, 0.18 to 0.50; <i>P</i><0.01); in non-reperfused subjects CCC was 0.52 (95% CI, 0.20 to 0.60; <i>P</i><0.001) and ICC was 0.60 (95% CI, 0.37 to 0.76; <i>P</i><0.001). No difference was observed between the mCTA and CTP predicted infarct volume in the test cohort (<i>P</i>=0.67).Conclusions A ML based mCTA model is able to predict brain tissue perfusion abnormality and follow-up infarction, comparable to CTP.