In the setting of acute ST-elevation myocardial infarction (STEMI), reperfusion therapy with primary percutaneous coronary intervention (PCI) performed by an experienced team or pharmacological reperfusion with thrombolytic therapy is highly recommended. Standard echocardiographic measurement of the left ventricular ejection fraction (LVEF) is widely used to assess left ventricular global systolic function. This study was designed to compare the assessment of global left ventricular function by standard LVEF and global longitudinal strain (GLS) in the two well-known reperfusion strategies. We conducted a retrospective single-center observational study in 50 patients with acute STEMI who underwent primary PCI (n = 25) and Tenecteplase (TNK)-based pharmacological reperfusion therapy (n = 25). The primary outcome was left ventricle (LV) systolic function after primary PCI, as assessed by two-dimensional (2D) GLS using speckle-tracking echocardiography (STE), as well as LVEF using standard 2D echocardiogram using Simpson's biplane method. Overall mean age was 53.7 ± 6.9 years with 88% male gender. The mean door-to-needle time was 29.8 ± 4.2 min in the TNK-based pharmacological reperfusion therapy arm, and the mean door-to-balloon time was 72.9 ± 15.4 min in the primary PCI arm. LV systolic function was significantly better in the primary PCI arm as compared to the TNK-based pharmacological reperfusion therapy, both by 2D STE (mean GLS: -13.6 ± 1.4 vs. -10.3 ± 1.2, P ≤ 0.001) and LVEF (mean LVEF: 42.2 ± 2.9 vs. 39.9 ± 2.7, P = 0.006). There were no significant differences in mortality and inhospital complications in both groups. Global LV systolic function is significantly better after primary coronary angioplasty as compared to TNK-based pharmacological reperfusion therapy when assessed by routine LVEF and 2D GLS in the setting of acute STEMI.