The aim of the present study was to assess the positive predictive value (PPV) of panoramic radiographic signs in the assessment of the relationship between impacted mandibular third molars (IMTMs) and the mandibular canal (MC). This cross-sectional study was conducted by reviewing 102 cone-beam computed tomography (CBCT) and panoramic radiographs of patients with IMTMs and radiographic signs of the contact of the IMTMs with the MC on panoramic radiographs (i.e., root apex darkening and interference with the white line). A positive relationship of the IMTM roots with the MC based on CBCT findings was recorded as the gold standard. The PPV of panoramic radiographic signs was calculated for the detection of the relationship of the IMTM root with the MC. The IMTMs were in contact with the MC on CBCT scans in 90.1% of the cases. The PPV of root apex darkening and the interference with the white line was found to be 89.09% (95% CI: (77.75, 95.88)) and 91.48% (95% CI: (79.62, 97.63)), respectively. The MC had a buccal position in 63.7%, and a lingual position in 35.2%, of the cases. The contact of IMTMs with the MC was more commonly seen in patients with a lingual position (100% of the samples). The IMTM root apex darkening and interference with the white line of the MC on panoramic radiographs had a high PPV for determination of the contact of IMTMs with the MC. Thus, presence of the above-mentioned risk factors indicates the need for subsequent 3D radiographic assessments.