The present study provides information about the evolution of the Sperchios River deltaic area over the last 6500 years. Coastal changes, due to natural phenomena and anthropogenic activities, were analyzed utilizing a variety of geospatial data such as historic records, topographic maps, aerial photos, and satellite images, covering a period from 4500 BC to 2020. A qualitative approach for the period, from 4500 BC to 1852, and a quantitative analysis, from 1852 to the present day, were employed. Considering their scale and overall quality, the data were processed and georeferenced in detail based on the very high-resolution orthophoto datasets of the area. Then, the multitemporal shorelines were delineated in a geographical information system platform. Two different methods were utilized for the estimation of the shoreline changes and trends, namely the coastal change area method and the cross-section analysis, by implementing the digital shoreline analysis system with two statistical approaches, the end point rate and the linear regression rate. Significant river flow and coastline changes were observed with the overall increase in the delta area throughout the study period reaching 135 km² (mean annual growth of 0.02 km²/yr) and the higher accretion rates to be detected during the periods 1805–1852, 1908–1945 and 1960–1986, especially at the central and north part of the gulf. During the last three decades, the coastline has remained relatively stable with a decreasing tendency, which, along with the expected sea-level rise due to climate change, can infer significant threats for the coastal zone in the near future.