Background: The recommended reperfusion treatment for individuals suffering from acute ST-elevation myocardial infarction (STEMI) is primary percutaneous coronary intervention (PCI). However, few hospitals offer 24-hour personnel for PCI procedures, and many lack PCI facilities. If primary PCI cannot be completed in a timely manner, thrombolytic treatment is given to eligible patients because reperfusion is a crucial strategy to reduce mortality and severe cardiovascular events in STEMI care, and the benefit is time-dependent. Objective: To compare routine early coronary angioplasty with ischaemia-guided angioplasty after successful thrombolysis in patients with acute anterior STEMI. Patients and methods: The study enrolled 100 patients presented to the Emergency Department of Ain Shams University hospitals and the National Heart Institute with acute anterior STEMI divided into two groups: Group A received routine early coronary angioplasty within 24 hours after thrombolysis, while Group B received ischaemia-guided angioplasty based on stress myocardial perfusion imaging. Results: Group A showed significantly lower rates of recurrent chest pain and need for urgent intervention compared to Group B, with no significant differences in heart failure, arrhythmias, major bleeding, or mortality during hospitalization. At three months, Group A had non-significantly lower rates of recurrent chest pain, need for urgent intervention, readmission, and mortality compared to Group B. The study highlights the importance of timely intervention, with Group A having an average time from thrombolytic initiation to angiography and subsequent PCI of 15 hours compared to 22 days in Group B. Group B achieved better Thrombolysis in Myocardial Infarction (TIMI) flow grades post-PCI, which may have offset the benefits of early intervention observed in Group A. Conclusion: Routine early invasive strategy after successful thrombolysis is associated with improved clinical outcomes compared to ischaemia-guided management, emphasizing the importance of timely intervention.