Background: The mandibular foramen (MF) is the anatomic landmark where the interior alveolar nerve enters the mandibular ramus, and the area of choice where anesthesia of this nerve is performed. The position of the MF can vary, and accurately establishing its location and topographic variations is of great importance for the successful anesthesia of the inferior alveolar nerve. Materials and Methods: We carried out two morphometric ex vivo studies concerning the topography of the MF, on dry human mandibles coming from dentate and completely edentulous human subjects of known age and gender and an in vivo morphometric study, through cone-beam computed tomography (CBCT) scans, concerning the topography of the MF in human subjects having Kennedy Class I mandibular edentulism. The morphological characteristics we investigated were: the distance between the MF and the anterior margin of the mandibular ramus (MF–AM distance), the distance between the MF and the posterior margin of the mandibular ramus (MF–PM distance), the distance between the MF and the inferior margin of the mandibular ramus (MF–IM distance), the distance between the MF and the temporal crest of the mandibular ramus (MF–TC distance), the distance between the MF and the superior margin of the mandibular ramus (MF–SM distance), and the vertical and transverse diameters of the MF. The results were statistically processed in Stata/MP13 software package using Student’s t-test and two-way analysis of variance (ANOVA). Results: Through direct morphometry on dentate dry human mandibles, the MF–AM and the MF–SM distances showed statistically significant differences for age, gender and for interactions, while the MF–PM and MF–IM distances showed statistically significant differences for age and for interactions. In the case of the MF–TC distance, the only significant difference observed was for the gender. No statistical significance was found for side, age, gender, and interactions in the cases of MF vertical and transverse diameters. Through direct morphometry on completely edentulous dry human mandibles, the MF–PM and MF–SM distances showed statistically significant differences for age, gender and for interactions, while the MF–AM, MF–IM, and MF–TC distances, as well as the MF vertical and transverse diameters showed statistically significant differences for age and for model (interactions). The results showed that MF is 2 mm closer to the anterior margin of the mandibular ramus after having lost teeth. Through imaging morphometry, the MF–PM distance and the vertical diameter of MF showed statistically significant differences for age, gender and for interactions, while the MF–AM, MF–IM, MF–SM and MF–TC distances, as well as the transverse diameter of MF showed statistically significant differences for age and for interactions. Comparing the results obtained by the three studies, we found no statistically significant differences in relation to the gender of the subjects. The MF–IM and MF–TC distances and the transverse diameter of MF showed statistically significant differences for age, study and for interactions, while the MF–AM, MF–PM and MF–SM distances, as well as MF vertical diameter showed statistically significant differences only for age and for interactions. Morphological symmetry was demonstrated through our three studies, no statistically significant differences being determined in relation to side. Conclusions: The results of this research should increase the level of awareness among dentists with respect to MF topography changes with loss of teeth and help dental practitioners in refining the inferior alveolar nerve block techniques.