Background and Objectives Tissue plasminogen activator (t-PA) within 4.5 hours from onset improves outcome in patients with ischemic stroke and has been recommended by several international guidelines. Since its approval in 1996, the debate among emergency physicians continues particularly around the result interpretation of the first positive randomized controlled trial, the National Institute of Neurological Disorders and Stroke (NINDS) clinical trial. This lack of consensus might negatively affect the delivery of effective stroke care. Here we aimed to assess the knowledge and attitude of Saudi emergency physicians toward t-PA use within 4.5 hours of onset in acute ischemic stroke. Methods A web-based, self-administered, locally designed questionnaire was sent to all emergency physicians practicing in the city of Riyadh from January to September 2017. Results Out of 450 emergency physicians, 122 from ten hospitals in Riyadh participated in the survey, with a 27% response rate. The majority of participants were men (78%), and their mean age was 40 ± 8 years. Half of the participants were board certified, and 36% were consultants. Half of the participants consider the evidence for t-PA use in stroke within 4.5 hours of stroke onset to be controversial, and 41% recommend against its use due to lack of proven efficacy (37%), the risk of hemorrhagic complications (35%), lack of stroke expertise (21%), and medicolegal liability (9%). Nearly half were willing to administer IV t-PA for ischemic stroke in collaboration with remote stroke neurology consultation if telestroke is implemented. Conclusion Our study detected inadequate knowledge and a negative attitude among Saudi emergency physicians toward t-PA use in acute stroke. This might negatively impact patient outcome. Therefore, we recommend developing urgent strategies to improve emergency physicians' knowledge, attitudes, and beliefs in the management of acute stroke.