Objectives This study aimed to analyze the association between the use of proton pump inhibitors (PPIs) and radiomorphometric parameters of trabecular and cortical bone of the mandible. Methods A total of 64 patients (37 females and 27 males) using PPIs (PPI group) and 64 age- and gender-matched healthy individuals (control group) were included in this study. The analyzed radiomorphometric parameters were fractal dimension (FD), mandibular cortical width (MCW), and mandibular cortical index (MCI). Results There were no significant differences in the mean FDs of selected regions and MCW between the two groups (p > 0.05). The mean MCW was 1.95 mm in the PPI group and 2 mm in the control group. The MCI C3 category, which represents the most porous state of the mandibular cortex, was 2.5 times more frequent in the PPI group (p = 0.002). PPI use duration did not correlate with FD or MCW. No significant differences were observed in FD, MCW, and MCI distribution according to PPI type (p > 0.05). Conclusions Although not all radiomorphometric parameters indicated osteoporotic effects of PPI use, the mandibular cortex of PPI users is prone to erosive defects.