Background Early recognition of large‐vessel occlusion in acute ischemic stroke is pivotal to ensuring timely and effective treatment. However, current prehospital evaluation strategies largely rely on stroke scales that lack sensitivity and specificity. Recently, a novel, portable, noninvasive brain perfusion ultrasound device (SONAS) was developed as a diagnostic aid and demonstrated robust correlation with magnetic resonance imaging–based brain perfusion imaging. The present study aimed to investigate the feasibility and diagnostic performance of the SONAS device in identifying alterations in cerebral blood flow in patients with acute ischemic stroke with suspected or known perfusion deficits. Methods We performed a phase II, single‐arm, prospective study using SONAS in a close timely relation to computed tomography perfusion imaging in subjects diagnosed with acute ischemic stroke and suspected or known large‐vessel pathology, presenting within 24 hours of symptom onset between April 2019 through December 2019. Performance end points included successful measurement of time‐to‐peak in each hemisphere and comparison of perfusion deficits measured by SONAS to the reference standard computed tomography perfusion imaging. Safety end points included frequency, severity, and outcome of adverse events. Results A total of 20 subjects were enrolled. Eighteen subjects (90%) had microbubble signals successfully detected on initial assessment by SONAS. The diagnostic accuracy of the SONAS device in identifying a perfusion deficit was 88.9%. The sensitivity was 14 of 15 (93.3%), and the specificity was 2 of 3 (66.7%). No adverse events were reported secondary to SONAS or the contrast agent used. Conclusion In this clinical study, we demonstrated that the SONAS system is a safe tool that can aid in identifying cerebral perfusion deficits in this selected population of patients with acute ischemic stroke with suspected or known perfusion deficits. Future studies should assess the efficacy and impact on clinical outcomes of using SONAS in a real‐world “in the field” setting on a large subset of patients with suspected stroke and in addition to prehospital stroke scales.