Dynamic advances in dentistry, especially in implantology has inspired researchers to carry out many studies investigating the topography of the mandibular canal and its ethnic differences. The aim of the study was a comparative analysis of variations in the position and topography of the mandibular canal based on radiographic images of human mandibles originating from modern and medieval skulls. Morphometric examination of 126 radiographs of skulls (92 modern and 34 medieval skulls) was included. The age and sex of individuals were determined based on the morphology of the skull, the obliteration of cranial sutures, and the degree of tooth wear. To define the topography of the mandibular canal on X-ray images, we took 8 anthropometric measurements. We observed significant differences in several parameters. The distance between the base of the mandible and the bottom of the mandibular canal, the distance between the top of the mandibular canal and the crest of the alveolar arch, and the height of the mandibular body. Significant asymmetry was found for two parameters of mandibles from modern skulls: the distance between the top of the mandibular canal and the crest of the alveolar arch at the level of the second molar (p < 0.05), and the distance between the mandibular foramen and the margin of the anterior mandibular ramus (p < 0.007). There were no significant differences between measurements taken on the right and left sides of the medieval skulls. Our study revealed differences in the position of the mandibular canal between modern and medieval skulls, confirming the presence of geographical and chronological differences between populations. Knowledge of variability in the position of the mandibular canal between different local populations is fundamental for the correct interpretation of findings from diagnostic radiological studies used in dental practice and in forensic odontology or analysis of archaeological bone materials.