Background: The anterior-middle superior alveolar (AMSA) anesthetic technique has been reported to be a less traumatic alternative to several conventional nerve blocks and local infiltration for anesthesia of the maxillary teeth, their periodontium, and the palate. However, its anatomic basis remains controversial. The present study aimed to determine if the pattern of cortical and cancellous bone density in the maxillary premolar region can provide a rationale for the success of the AMSA anesthetic technique.Method: Cone-beam computed tomography scans of 66 maxillary quadrants from 34 patients (16 men and 18 women) were evaluated using a volumetric imaging software for cortical and cancellous bone densities in three interdental regions between the canine and first molar. Bone density was measured in Hounsfield units (HU) separately for the buccal cortical, palatal cortical, buccal cancellous, and palatal cancellous bones. Mean HU values were compared using the Mann-Whitney U test and one-way ANOVA with post-hoc analysis. Results: Cancellous bone density was significantly lower (P ≤ 0.001) in the palatal half than in the buccal half across all three interdental regions. However, there was no significant difference (P = 0.106) between the buccal and palatal cortical bone densities at the site of AMSA injection. No significant difference was observed between the two genders for any of the evaluated parameters. Conclusions The palatal half of the cancellous bone had a significantly lower density than the buccal half, which could be a reason for the effective diffusion of the anesthetic solution following a palatal injection during the AMSA anesthetic technique.