Objectives: This study aimed to evaluate the accuracy of CBCT-based volumetric measurements of maxillary defects and to investigate the effects of different CBCT devices, kVp settings, and segmentation software on measurement accuracy. Methods: CBCT images from eight patients with maxillary defects were used to generate 3D-printed models for volumetric assessment. Two CBCT systems (Largev Smart and Planmeca Promax) were evaluated at three different kVp settings. Volume calculations were conducted using ITK-SNAP version 4.2.2 and 3D Doctor version 4.0 software, while micro-CT served as the gold standard (GS) for comparison. Statistical analysis included a three-way ANOVA to assess the effect of CBCT parameters and software on volumetric accuracy. Additionally, post-hoc Tukey HSD analysis was performed to identify specific differences between kVp groups, and Pearson correlation analysis was used to evaluate consistency with the GS. Significance level was set at p < 0.05. Results: Higher kVp settings significantly improved volumetric accuracy, with 100 kVp yielding the smallest deviations (−3.77%) from the GS. Tukey HSD analysis revealed significant differences between 60–80 kVp (p = 0.008), 60–100 kVp (p < 0.001), and 80–100 kVp (p = 0.041), confirming the influence of kVp on accuracy. No significant differences were observed between CBCT devices or software programs (p > 0.05). A strong positive correlation (r = 0.96) between CBCT-derived and micro-CT volumes confirmed CBCT’s reliability for volumetric assessments (p < 0.001). Conclusions: CBCT provides accurate volumetric measurements of maxillary defects, particularly at higher kVp settings. These findings support its clinical application for preoperative planning and postoperative evaluation, offering a cost-effective alternative to micro-CT.