Objective <p>The aim of this retrospective comparative cross-sectional study was to evaluate the prevalence of radiographically detected pulp stones on panoramic radiographs and investigate their possible association with systemic diseases.</p> Methods <p>A total of 1,000 panoramic radiographs obtained from the archive of the Faculty of Dentistry at Fırat University between 2019 and 2025 were retrospectively analyzed. Participants were divided into four groups: control (<i>n</i> = 400), cardiovascular disease (<i>n</i> = 200), diabetes mellitus (DM) (<i>n</i> = 200), and kidney stone (<i>n</i> = 200). The presence of radiographically detected pulp stones, tooth location (according to the FDI system), and age groups were recorded. Statistical analyses included the chi-square test and age- and sex-adjusted binary logistic regression analyses. Inter- and intra-observer agreement was assessed using Cohen’s kappa coefficient.</p> Results <p>The overall prevalence of radiographically detected pulp stones was 28.1%. The prevalence was significantly higher in the diabetes mellitus (38.5%), cardiovascular disease (34.0%), and kidney stone (31.0%) groups compared with the control group (18.5%) (<i>p</i> &lt; 0.001). In the unadjusted analysis, the odds of pulp stone presence were significantly higher in the diabetes mellitus (OR = 2.25), cardiovascular disease (OR = 1.89), and kidney stone groups (OR = 1.62). However, these crude associations changed substantially after adjustment for age and sex, with adjusted estimates moving below the null value, suggesting substantial confounding by age and limited comparability between the disease and control groups. Age remained the strongest independent predictor in the adjusted model (<i>p</i> &lt; 0.001). The highest prevalence was observed in the 46–60 age group (41.0%), and females showed a significantly higher prevalence than males (<i>p</i> = 0.04). Radiographically detected pulp stones were most frequently observed in the maxillary and mandibular first molars.</p> Conclusion <p>Radiographically detected pulp stones were more frequently observed in individuals with systemic diseases, particularly diabetes mellitus and cardiovascular disease. However, although higher crude prevalence rates were observed in the systemic disease groups, these associations changed substantially after adjustment for age and sex, with adjusted estimates moving below the null value, suggesting substantial confounding by age and limited comparability between the disease and control groups. Due to the retrospective cross-sectional design and the limitations of panoramic radiography, the results should be interpreted cautiously. Further prospective multicenter studies using advanced imaging modalities are needed to clarify these associations.</p>