Background: Acute systolic heart failure (ASHF) is one of the most serious complications of the acute coronary syndrome (ACS), and increases the likelihood of adverse clinical outcomes. It remains unclear whether the use of non-invasive ventilation (NIV) could improve symptoms and reduce mortality in patients with ASHF derived from ACS. Methods: Data on biological, clinical, and demographic factors, as well as therapy data, were collected from patients with ASHF in the cardiac department. A total of 1257 ACS patients with ASHF were included in the study. Patients were divided into two groups. The control group received standard oxygen therapy. The comparison group consisted of those who underwent NIV as part of their immediate care. During hospitalization and at follow-up, information on both groups was systematically compared. Results: In comparison with the control group, mean 24-hour urine output was found to be significantly higher in the NIV group. A significant reduction in the duration of symptoms was observed among patients in the NIV group from the time of admission until relief of dyspnea. Heart rate, C-reactive protein, estimated glomerular filtration rate, and N-terminal prohormone of brain natriuretic peptide (NT-proBNP) was also improved, compared with those in the control group. The NIV group was found to have a higher survival rate. NIV was independently related to all-cause mortality in 1-year follow-up (hazard ratio, 0.674; p = 0.045). Conclusions: Our study shows that NIV, as compared with standard oxygen therapy, has a beneficial impact on heart rate, metabolic balance, and relief of dyspnea in ACS patients with ASHF which results in reduced intubation rate, duration of in-hospital stay, and 1-year mortality.