(i) Objective: Changes in the mesiodistal axial angulations of teeth with orthodontic treatment have been a topic of interest in orthodontics for many years, although it has not been clarified enough yet. Therefore, this present study aimed to compare mesiodistal axial angulations of canine and first molar teeth by measuring from pre- and post-treatment panoramic radiographs in different types of orthodontic malocclusions. (ii) Materials and Methods: In the study, the mesiodistal axial angulation angles of the lower–upper canines (teeth numbered 13, 23, 33, and 43) and first molars (teeth numbered 16, 26, 36, and 46) were compared on panoramic radiographs taken pre- (T0) and post- (T1) orthodontic treatment of 353 patients: 237 female (mean age 14.74 ± 2.96) and 116 male (mean age 14.44 ± 2.50), who had not received any prior orthodontic treatment. The groups were formed according to pre-/post-treatment, gender, angle classification, skeletal classification, bilaterally first premolar extraction/non-extraction, and the use/non-use of miniscrews in the extraction cases. The mesiodistal angulations between the long axes of both the lower and upper canines and first molars and the interorbital plane were measured separately and recorded. The reliability analysis between the repeated measurements was evaluated using the intraclass correlation coefficient (ICC). For statistical analysis, a paired sample t-test and Wilcoxon test were used for the normally and non-normally distributed data, respectively. For the between-groups comparison, independent sample t-test and one-way ANOVA were used for normally distributed data, while the Mann–Whitney U and Kruskal–Wallis tests were used for non-normally distributed data. A value of p < 0.05 was considered statistically significant. (iii) Results: ICCs showed excellent reliability, ranging from 0.804 to 0.913 in other teeth, yet were good in tooth 43 (ICC = 0.712). Regardless of the groups, statistically significant differences were found between the T0 and T1 angulations for all teeth, except teeth 13 and 16. In all groups, the increase in the angulations of teeth 33 and 43 and the decrease in the angulations of teeth 36 and 46 (except skeletal class 3) were found to be statistically significant. The T0 and T1 angulation changes in the miniscrews in the used and non-used groups in extraction cases were similar to the differences found in all teeth, regardless of the groups. There was no significant difference between gender, skeletal classes, and angle classes in the amounts of change in the mesiodistal angulations. (iv) Conclusion: It was concluded that orthodontic treatment caused significant changes in the mesiodistal axial angulation of the canine and the first molar teeth. Furthermore, the fact that the angulations tended to increase in the lower canine teeth and decrease in the lower first molar teeth revealed the importance of tooth movement control, especially in orthodontic mechanics in the mandibula.