Background and Objectives: Regardless of the improvement in key recommendations in non-ST-elevation myocardial infarction (NSTEMI), the prevalence of total occlusion (TO) of infarct-related artery (IRA), and the impact of TO of IRA on outcomes in patients with NSTEMI, remain unclear. Aim: The study aimed to assess the incidence and predictors of TO of IRA in patients with NSTEMI, and its clinical significance. Material and Methods: The study was a single-center retrospective cohort analysis of 399 consecutive patients with NSTEMI (293 male, mean age: 71 ± 10.1 years) undergoing percutaneous coronary intervention. The study population was categorized into patients with TO and non-TO of IRA on coronary angiography. In-hospital and one-year mortality were analyzed. Results: TO of IRA in the NSTEMI population occurred in 138 (34.6%) patients. Multivariate analysis identified the following independent predictors of TO of IRA: left ventricular ejection fraction (odds ratio (OR) 0.949, p < 0.001); family history of coronary artery disease (CAD) (OR 2.652, p < 0.001); and high-density lipoprotein (HDL) level (OR 0.972, p = 0.002). In-hospital and one-year mortality were significantly higher in the TO group than the non-TO group (2.8% vs. 1.1%, p = 0.007 and 18.1% vs. 6.5%, p < 0.001, respectively). The independent predictors of in-hospital mortality were: left ventricular ejection fraction (LVEF) at admission (OR 0.768, p = 0.004); and TO of IRA (OR 1.863, p = 0.005). Conclusions: In the population of patients with NSTEMI, TO of IRA represents a considerably frequent phenomenon, and corresponds with impaired outcomes. Therefore, the utmost caution should be paid to prevent delay of coronary angiography in NSTEMI patients with impaired left ventricular systolic function, metabolic disturbances, and a family history of CAD, who are at increased risk of TO of IRA.