This study investigated the temporal and spatial characteristics of PM2.5 and the related human health impacts in various environmental areas of South Korea during high-concentration days in winter (February 15−March 15, 2019). These analyses were performed using PM2.5 observations and numerical modeling, which included the Community Multi-scale Air Quality model (CMAQ v5.3.2) and the Environmental Benefits Mapping and Analysis Program-Community Edition (BenMAP-CE v1.5.0.4). The mean PM2.5 concentrations observed on high-concentration days (50.1 μg m−3 in the southeastern area to 65.2 μg m−3 in the southwestern area) were 2.1–2.7 times higher than those observed on non-high-concentration days (18.4 μg m−3 in the southeastern area to 27.0 μg m−3 in the northwestern area). In addition, many premature deaths and high premature death rates from respiratory and cardiovascular diseases attributable to high PM2.5 levels were mostly distributed in the western regions of South Korea. These regional differences may be due to a combination of local meteorology and emissions and/or the long-range transport of pollutants. However, the magnitude of these premature deaths varied across areas, genders, and age groups due to differences in PM2.5 concentrations and mortality rates. The number of premature deaths from cardiovascular diseases due to increased PM2.5 levels was slightly higher than that from respiratory diseases, owing to the higher mortality rates. The health impact of cardiovascular diseases was estimated to be more severe in women than in men, and vice versa for respiratory diseases.